Proteasome chymotrypsin-like inhibition using PI-1833 analogs

ABSTRACT

Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring&#39;s para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of prior filed InternationalApplication, Serial Number PCT/US2012/030574 filed on Mar. 26, 2012,which claims priority to U.S. Provisional Patent Application No.61/467,051, entitled “Proteasome Chymotrypsin-Like Inhibition usingPI-1833 Analogs”, filed on Mar. 24, 2011, and U.S. Provisional PatentApplication No. 61/471,472, entitled “Proteasome Chymotrypsin-LikeInhibition using PI-1833 Analogs”, filed on Apr. 4, 2011, the contentsof which are herein incorporated by reference.

GOVERNMENT SUPPORT STATEMENT

This invention was made with Government support under Grant No. CA118210awarded by the National Institute of Health. The Government has certainrights in the invention.

FIELD OF INVENTION

This invention relates to cancer treatment. Specifically, the inventionprovides novel compounds for inhibiting the proteasome for inhibitingtumor growth.

BACKGROUND OF THE INVENTION

Current tumor treatments include radiotherapy, chemotherapy, surgicalresection, hormone therapy, or a combination of these treatments.Precise control of protein turnover is essential to cellular survival.In eukaryotes, the majority of protein degradation occurs through theUPP, which consists of the ubiquitin-conjugating system and theproteasome (Yamasaki, L. and Pagano, M. Curr. Opin. Cell Biol. 2004, 16,623-628. Ciechanover, A.; Orian, A.; Schwartz, A. L. J Cell BiochemSuppl 2000, 34, 40-51; Ciechanover, A. Cell 1994, 79, 13-21;Hochstrasser, M. Curr. Opin. Cell Biol. 1995, 7, 215-223; Coux, O.;Tanaka, K.; Goldberg, A. L. Annu Rev Biochem 1996, 65, 801-847;Baumeister, W., et al. Cell 1998, 92, 367-380; Murata, S., et al. Nat.Rev. Mol. 2009, 10, 104-115). The proteasome is a massive multicatalyticprotease comprising a 20S multisubunit structure which is capped by the19S regulatory complex at each end, forming the core of the 26Sproteasome, the major extralysosomal mediator of protein degradation(Groll, M., et al. Nature (London) 1997, 386, 463-471; Adams, J. Nat.Rev. Cancer 2004, 4, 349-360). The three main catalytic activities ofthe proteasome; peptidylglutamyl peptide hydrolysing (PGPH),trypsin-like (T-L), and chymotrypsin-like (CT-L), are mediated by threedistinct catalytic β-1, β-2, and β-5 subunits respectively (Groll, M.;Bekers, C. R.; Ploegh, H. L.; Ovaa, H. Structure, 2006, 14, 451-456).The proteasome is responsible for degrading a large number of cellularproteins (Lowe J., et al. Crystal structure of the 20S proteasome fromthe archaeon T. acidophilum at 3.4 Å resolution. Science 1995;268:533-9). The eukaryotic proteasome possesses at least three distinctactivities: chymotrypsin-like (cleavage after hydrophobic residues),trypsin-like (cleavage after basic residues), and caspase-like (cleavageafter acidic residues). These target proteins are first tagged withubiquitin in order to be degraded by the proteasome.

Ubiquitination is mediated by the sequential action of an E1Ub-activating enzyme, an E2 Ub-conjugating enzyme, and an E3 Ub-ligase.Once Ub-tagged, proteins bind to subunits in the 19S regulatory cap ofthe proteasome, where they are deubiquitinated and unfolded in an energydependent manner. These are then fed into the catalytic inner chamber ofthe 20S complex, which generates peptides of 3-22 amino acids in size(Vorhees, et al., The proteasome as a target for cancer therapy. ClinCan Res. 2003 Dec. 15; 9: 6316-6325).

The ATP-dependent ubiquitin-proteosome pathway is responsible for thecontrolled degradation of proteins in eukaryotic cells (Hochstrasser,Ubiquitin, proteasomes, and the regulation of intracellular proteindegradation. Curr. Opin. Cell Biol. 1995, 7, 215-23; Yamasaki andPagano, Cell cycle, proteolysis and cancer. Curr. Opin. Cell Biol. 2004,16, 623-628; Coux, et al. Structure and functions of the 20S and 26Sproteasomes. Annu Rev Biochem 1996, 65, 801-47; Ciechanover, et al. Theubiquitin-mediated proteolytic pathway: mode of action and clinicalimplications. J. Cell. Biochem. 2000, 40-51; Ciechanover, Theubiquitin-proteasome proteolytic pathway. Cell (Cambridge, Mass.) 1994,79, 13-21; Baumeister, et al. The proteasome: paradigm of aself-compartmentalizing protease. Cell 1998, 92, 367-80). The 26Sproteosome is a multifunctional complex, consisting of a 19S regulatoryparticle (RP) and a 20S core particle (CP) (Groll, et al. Structure of20S proteasome from yeast at 2.4.ANG. resolution. Nature (London) 1997,386, 463-471). The three main catalytic activities of the proteasome;peptidylglutamyl peptide hydrolysing (PGPH), trypsin-like (T-L), andchymotrypsin-like (CT-L), are mediated by three distinct catalytic β-1,β-2, and β-5 subunits respectively (Groll and Huber, Inhibitors of theeukaryotic 20S proteasome core particle: a structural approach. Biochim.Biophys. Acta, Mol. Cell. Res. 2004, 1695, 33-44).

In a broad range of cell culture models, proteasome inhibitors rapidlyinduce tumor cell apoptosis, selectively activating the cell deathprogram in oncogene-transformed, but not normal or untransformed cells,and are able to trigger apoptotic death in human cancer cells that areresistant to various anticancer agents (Adams J. Preclinical andclinical evaluation of proteasome inhibitor PS-341 for the treatment ofcancer. Curr Opin Chem Biol 2002; 6:493-500; Dou Q., Goldfarb R.Evaluation of the proteasome inhibitor MLN-341 (PS-341). IDrugs 2002;5:828-834). Inhibition of the chymotrypsin-like, but not thetrypsin-like, activity has been found to be associated with induction oftumor cell apoptosis.

Apoptosis is a highly conserved cellular suicide program inmulticellular organisms from worms to humans. This cellular deathprogram serves as a means to maintain multicellular organisms bydiscarding damaged and undesirable cells. Faulty execution of apoptosis,including either excessive cell death or insufficient cell death, is afactor in many disease states including AIDS and cancer (Jacobson M., etal. Programmed cell death in animal development. Cell 1997; 88:347-54;Song Z., Steller H. Death by design: mechanism and control of apoptosis.Trends Cell Biol 1999; 9:M49-52). Apoptosis features several distinctevents and morphological changes, such as loss of the mitochondrialmembrane potential, proteolytic dismantling of cellular components, DNAfragmentation, and cellular condensation into apoptotic bodies that areremoved by phagocytes (Green D., Reed J. Mitochondria and apoptosis.Science 1998; 281:1309-12; Earnshaw W., et al. Mammalian caspases:structure, activation, substrates, and functions during apoptosis. AnnuRev Biochem 1999; 68:383-424; Bratton S., et al. Protein complexesactivate distinct caspase cascades in death receptor and stress-inducedapoptosis. Exp Cell Res 2000; 256:27-33; Wyllie A., et al. Cell death:the significance of apoptosis. Int Rev Cytol 1980; 68:251-306). As adistinct series of cellular pathways, apoptosis potentially offersunique targets for chemotherapeutic intervention. It has been suggestedthat cancer cells are more sensitive to several apoptosis-inducingstimuli than normal cells, including proteasome inhibitors and thoseaffecting cellular division (Adams J. Potential for proteasomeinhibition in the treatment of cancer. Drug Discov Today 2003; 8:307-15;Dou Q., Li B. Proteasome inhibitors as potential novel anticanceragents. Drug Resist Update 1999; 2:215-223; Almond J B, Cohen G M. Theproteasome: a novel target for cancer chemotherapy. Leukemia 2002;16:433-43; Goldberg A L. Functions of the proteasome: the lysis at theend of the tunnel. Science 1995; 268:522-3; Dou Q., et al. Interruptionof tumor cell cycle progression through proteasome inhibition:implications for cancer therapy. In Progress in Cell Cycle Research.Meijer L, Jezequel A, Roberge M, (eds.) Life in Progress Editions,Roscoff, 2003; pp. 441-446). Several regulatory proteins involved incell cycle and apoptosis processes, such as cyclins, bcl-2 familymembers, and p53, are degraded by the ubiquitin-proteasome pathway (AnB., et al. Novel dipeptidyl proteasome inhibitors overcome Bcl-2protective function and selectively accumulate the cyclin-dependentkinase inhibitor p27 and induce apoptosis in transformed, but notnormal, human fibroblasts. Cell Death Differ 1998; 5:1062-75; Lopes U.,et al. p53-dependent induction of apoptosis by proteasome inhibitors. JBiol Chem 1997; 272:12893-6).

Owing to the central role of proteosome in maintaining homeostasis andhence its key position in many cellular processes, the development ofproteasome inhibitors for CT-L activity has been the subject ofconsiderable interest in the treatment of cancer due to its criticalrole in the degradation of apoptotic and tumor suppressor proteins(Borissenko and Groll, 20S Proteasome and Its Inhibitors:Crystallographic Knowledge for Drug Development. Chem. Rev. (Washington,D.C., U.S.) 2007, 107, 687-717; Genin, et al. Proteasome inhibitors:recent advances and new perspectives in medicinal chemistry. Curr. Top.Med. Chem. (Sharjah, United Arab Emirates) 2010, 10, 232-256). Theantitumor activity of proteasome inhibitors has been confirmed by theresults of bortezomib, a potent and selective dipeptidyl boronic acidproteasome inhibitor (Sunwoo J., et al. Novel proteasome inhibitorPS-341 inhibits activation of nuclear factor-kappa B, cell survival,tumor growth, and angiogenesis in squamous cell carcinoma. Clin CancerRes 2001; 7:1419-28) that selectively inhibits the CT-L activity of 20Sproteasome (Jung, L., et al. Oncology 2004, 18, 4-13; Lara, P. N., etal. Semin. Oncol. 2004, 31, 40-46. Adams, J. Semin. Oncol. 2001, 28,613-619).

The proteasome inhibitors currently in the clinic are derived from 3structural classes, seen in FIG. 1: In the first class, Bortezomib,which is a dipeptide boronic acid, was the first clinically approvedproteasome inhibitor (Groll, et al. Snapshots of theFluorosalinosporamide/20S Complex Offer Mechanistic Insights for FineTuning Proteasome Inhibition. J. Med. Chem. 2009, 52, 5420-5428; Groll,et al. Crystal structure of epoxomicin:20S proteasome reveals amolecular basis for selectivity of a′,b′-epoxyketone proteasomeinhibitors. J. Am. Chem. Soc. 2000, 122, 1237-1238). Similar toBortezomib, MLN9708 (Kupperman, et al. Evaluation of the proteasomeinhibitor MLN9708 in preclinical models of human cancer. Cancer Res2010, 70, 1970-80; Kupperman, et al. Evaluation of the proteasomeinhibitor MLN9708 in preclinical models of human cancer. [Erratum todocument cited in CA152:517050]. Cancer Res. 2010, 70, 3853; Lawrence,et al. Building on bortezomib: second-generation proteasome inhibitorsas anti-cancer therapy. Drug Discov Today 2010, 15, 243-9) (a modifieddipeptidyl boronic acid which hydrolyses immediately in plasma) andCEP-18770 (Dorsey, et al. CEP-18770: Discovery of a Potent, Selectiveand Orally Active Proteasome Inhibitor for the Treatment of Cancer.Frontiers in CNS and Oncology Medicinal Chemistry, ACS-EFMC, Siena,Italy, Oct. 7-9 2007, COMC-027; Piva, et al. CEP-18770: a novel, orallyactive proteasome inhibitor with a tumor-selective pharmacologic profilecompetitive with bortezomib. Blood 2008, 111, 2765-2775; Sterz, et al.The potential of proteasome inhibitors in cancer therapy. Expert Opin.Invest. Drugs 2008, 17, 879-895) are also boronic acid derivatives. Thesecond class includes β-lactone salinosporamide A (Fuchs, Proteasomeinhibition as a therapeutic strategy in patients with multiple myeloma.Mult. Myeloma 2009, 101-125; Lam, et al. From natural products toclinical trials: NPI-0052 (salinosporamide A), a marineactinomycete-derived anticancer agent. Nat. Prod. Chem. Drug Discovery2010, 355-373) (represented by NPI-0052) is a marine microbial naturalproduct. The third class includes tetrapeptide epoxyketone carfilzomib(Zhou, et al. Design and Synthesis of an Orally Bioavailable andSelective Peptide Epoxyketone Proteasome Inhibitor (PR-047). J. Med.Chem. 2009, 52, 3028-3038), which is related to the natural productepoxomicin. Each inhibitor class reacts with the proteasome N-terminalthreonine active sites by a distinct mechanism. Peptide boronic acids(Bortezomib, MLN9708 and CEP-18770) form a slowly reversible tetrahedraladduct with the OH group of the catalytic Thr-1 (Groll, et al. CrystalStructure of the Boronic Acid-Based Proteasome Inhibitor Bortezomib inComplex with the Yeast 20S Proteasome. Structure (Cambridge, Mass.,U.S.) 2006, 14, 451-456). For the β-lactone NPI-0052, attack of thelactone ring by catalytic Thr-1²³ forms an ester bond (that undergointramolecular rearrangement) which makes this compound an irreversibleinhibitor. The epoxyketone (Groll, et al. Crystal structure ofepoxomicin:20S proteasome reveals a molecular basis for selectivity ofa′,b′-epoxyketone proteasome inhibitors. J. Am. Chem. Soc. 2000, 122,1237-1238) moiety of Carfilzomib reacts with the OH and the α-aminogroup of Thr-1 to form 2 covalent bonds, making the inhibition alsoirreversible.

Proteasome inhibitors are classified as reversible or irreversibleinhibitors according to their chemical structure and mechanism ofinhibition. Irreversible/covalent and slow reversible inhibitors asdescribed above possess a chemically reactive group that bind toproteasome covalently; whereas non-covalent and rapidly reversibleinhibitors inhibit the proteasome through a network of interactions(hydrophobic, hydrogen bonds, electrostatic and/or van der Waals).Examples of reversible proteosome inhibitors include Ritonavir(Schmidtke, et al. How an inhibitor of the HIV-I protease modulatesproteasome activity. J. Biol. Chem. 1999, 274, 35734-35740), severalbenzylstatine derivatives (Furet, et al. Structure-Based optimization of2-aminobenzylstatine derivatives: potent and selective inhibitors of thechymotrypsin-Like activity of the human 20S proteasome. Bioorg. Med.Chem. Lett. 2002, 12, 1331-1334), 5-trimethoxy-L-phenylalaninederivatives (Furet, et al. Entry into a New Class of Potent ProteasomeInhibitors Having High Antiproliferative Activity by Structure-BasedDesign. J. Med. Chem. 2004, 47, 4810-4813), lipopeptides (Basse, et al.Development of lipopeptides for inhibiting 20S proteasomes. Bioorg. Med.Chem. Lett. 2006, 16, 3277-3281), TMC-95A derivatives (Kohno, et al.Structures of TMC-95A-D: Novel proteasome inhibitors from Apiosporamontagnei Sacc. TC 1093. J. Org. Chem. 2000, 65, 990-995) andfluorinated pseudopeptides (Formicola, et al. Novel fluorinatedpseudopeptides as proteasome inhibitors. Bioorg. Med. Chem. Lett. 2009,19, 83-86). Since non-covalent inhibitors do not have a reactive moiety,which is often associated with metabolic instability, poor specificity,and excessive reactivity, they have the advantage of exerting fewer sideeffects over the covalent and irreversible ones. It has been shown thatthe proteasome activity recovers at the same rate with irreversibleinhibitors as with covalent and slowly reversible inhibitors, presumablydue de novo proteasome synthesis. The clinical advantages/benefits ofnon-covalent and reversible proteasome inhibitors in cancer treatmentare not well understood. We have been actively engaged in the discoveryof novel proteasome inhibitors (Lawrence, et al. Synthesis andbiological evaluation of naphthoquinone analogs as a novel class ofproteasome inhibitors. Bioorg. Med. Chem. 2010, 18, 5576-5592; Ge, etal. Discovery and Synthesis of Hydronaphthoquinones as Novel ProteasomeInhibitors. J. Med. Chem., 2012 Mar. 8; 55(5):1978-98. Epub 2012 Feb.14).

The potent proteasome inhibitors reported to date have been developed asaldehydes, boronates, vinylsulfones and expoxyketones and thesecompounds function through covalent modification of the N-terminalthreonine residue of β-5 subunit. However, toxicity and tumor cellresistance against Bortezomib, as well as other proteasome inhibitors,demand the development of improved and selective proteasome inhibitors.

SUMMARY OF THE INVENTION

Small, drug-like synthetic proteasome inhibitors that are selective forcancer over normal cells are rare, but clearly would have a potentialadvantage over the existing inhibitors. PI-1833 and PI-1840 are smalldrug-like compounds that do not contain any reactive moieties. Thesecompounds have use as an irreversible proteosome inhibitor. As such, acompound comprising the formula

has been developed, which may be used in some embodiments as aproteasome inhibitor. The R_(A) moiety is optionally

wherein R₁ can be H, ethyl, isopropyl, isobutyl, CH₂CH₃, Br, Ph, F,ortho-CH₃, meta-CH₃, para-CH₃, CF₂H, CF₃, F, Cl, Br, NH₂, CN, OX, OH,C₆H₁₀, C₆H₁₃, C₅H₁₁, C₄H₉, C₃H₇, or NO₂; and R₄ can be H, alkyl methyl,aryl methyl, OH, OCH₃, or NH₂. In particular, the R₁ moiety isoptionally para-CH₃, CF₃, Cl, C₃H₇, C₄H₉, or isobutyl. Where the R₁moiety is OX, X is an aryl or alkyl group.

The R_(B) is optionally

wherein R₂ is H, Cl, ortho-CH₃, meta-CH₃, para-CH₃, CF₃, F, orisopropyl. In specific embodiments, the R₁ and R₂ moieties are not thesame group. R_(C) is a heterocyclic aromatic five-member ring structure,wherein the heterocyclic aromatic five-member ring structure furthercomprises at least one heteroatom consisting of O, N, or S. In someembodiments, the heterocyclic aromatic five-member ring structure is

R₃ can be H, isopropyl, or isobutyl, and R_(D) can be H, alkyl, NH, OH,or OX, where X is an aryl or alkyl. In specific embodiments of thecompound, R₁ is para-CH₃, CF₃, or Cl; R₃ is CH₂(CH₃)₂, or CH₂CH(CH₃)₂;R₄ is H; R₅ is H; and R₂ is H, Cl, CF₃, or CH₃. The compound isoptionally an S-enantiomer.

Compounds of formula II are also disclosed, as shown by

where the R₁ moiety is either ortho-CH₃, meta-CH₃, para-CH₃, CF₂H CF₃,F, Cl, Br, OH, NH₂, CN, NO₂, C₆H₁₀, C₆H₁₃, C₅H₁₁, C₄H₉, C₃H₇, OX, or H.The R_(C) moiety is a heterocyclic ring structure, such as

The R_(B) attached to the heterocyclic ring structure is optionally

where R₂ is H, Cl, ortho-CH₃, meta-CH₃, para-CH₃, CF₃, F, or isopropyl.In specific embodiments, the R₂ moiety is Cl, ortho-CH₃, meta-CH₃,para-CH₃, CF₃, F, or isopropyl. In other embodiments of the compounds,the R_(C) moiety is

where R₆ is ortho CH₃, meta CH₃, para CH₃, CF₃, OH, NH₂, CN, NO₂, OX,Cl, or H, and X is an alkyl or aryl. The R₃ moiety is optionallyCH(CH₃)₂, cyclopropyl, CH₂CH(CH₃)₂, CH₂CH₃, OH, or H, the R₄ moietyalkyl methyl, aryl methyl, OH, OMe, or NH₂, and the R_(D) moiety can beH, alkyl, NH, OH, OX, where X is an alkyl or aryl. The compound isoptionally an S-enantiomer.

The compounds of the invention may be used to inhibit thechymotrypsin-like activity of proteasome, by administering at least oneof the compounds disclosed above.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the invention, reference should be made tothe following detailed description, taken in connection with theaccompanying drawings, in which:

FIG. 1 is an illustration of the structures of clinically advancedproteasome inhibitors: Bortezomib (in clinic), MLN9708 (phase I),Carfilzomib (phase II), CEP-18770 (phase I) and NPI-0052 (phase I).

FIG. 2 is an illustration of an exemplary new compound, PI-1833,identified as a proteasome inhibitor.

FIG. 3 is a diagram illustrating the synthesis of PI-1833. Reagents andconditions; a DIPEA, DCM, RT, 24 h, 81%, b toluene, reflux, 12 h, 100%,c K₂CO₃, CH₃CN, reflux, 30 min, 91%, d K₂CO₃, CH₃CN, reflux, 12 h, 90%;or K₂CO₃, acetone, reflux, 12 hr, 90%, e NaOH, THF, reflux, 30 min, 92%;or NaOH, ethanol, reflux, 30 min, 92%, f SOCl₂, benzene, reflux, 3 h,94%, g Et₃N, THF, RT, 15 min, 88%.

FIG. 4 is a diagram of PI-1833 structure modifications for firstgeneration Analogs of PI-1833.

FIG. 5 is a diagram illustrating the synthesis of isopropyl-modifiedPI-1833 analogs. Reagents and conditions: a Et₃N, RT, 15 min., 88%.

FIG. 6 is a synthetic route to compound 1, and libraries 11 and 12.Reagents and conditions: a Ethyl bromoacetate, K₂CO₃, CH₃CN, reflux, 12h. b. tert-Butyl bromoacetate, DMF, 80° C., 14 h c. Ethyl bromoacetate,K₂CO₃, DMF, RT, 14 h. d. NaOH, THF, reflux, 30 min. e. CF₃COOH, DCM,r.t., 2 h (R=^(t)Bu). f. SOCl₂, benzene, reflux, 3 h. g. NH₂OH.HCl,Na₂CO₃, Water, 70° C., 14 h. h. Chloroacetyl chloride, acetone, 30 min.i. toluene, reflux, 2 h. j. Isopropylamine, K₂CO₃, CH₃CN, reflux, 30min. k. Et₃N, THF, 15 min. Library information is in Table 1 for library11, Table 2 for library 12, or as follows:

Library 5  5a R₁ = para-CH₃—Ph  5b R₁ = para-CF₃—Ph  5c R₁ = Ph  5d R₁ =para-Cl—Ph  5e R₁ = para-phenyl-Ph  5f R₁ = para-F—Ph  5g R₁ =6-bromonaphthalene  5h R₁ = meta-methyl-Ph  5i R₁ = ortho-methyl-Ph  5jR₁ = para-ethyl-Ph  5k R₁ = para-propyl-Ph  5l R₁ = para-butyl-Ph  5m R₁= para-pentyl-Ph  5n R₁ = para-hexyl-Ph  5o R₁ = para-cyclohexyl-Ph  5pR₁ = para-isopropyl-Ph  5q R₁ = para-isobutyl-Ph  5r R₁ =para-^(t)butyl-Ph  5s R₁ = para-OH—Ph  5t R₁ = para-COOH—Ph Library 1010a R₂ = para-CH₃—Ph, R₃ = isopropyl 10b R₂ = para-CF₃—Ph, R₃ =isopropyl 10c R₂ = Ph, R₃ = isopropyl 10d R₂ = para-Cl—Ph, R₃ =isopropyl 10e R₂ = ortho-pyridyl, R₃ = isopropyl 10f R₂ = meta-pyridyl,R₃ = isopropyl 10g R₂ = para-pyridyl, R₃ = isopropyl 10h R₂ =5-substituted pyrimidine, R₃ = isopropyl 10i R₂ = 2-substitutedpyrimidine, R₃ = isopropyl 10j R₂ = para-pyridyl, R₃ = isopropyl 10k R₂= para-CH₃—Ph, R₃ = methyl 10l R₂ = para-CH₃—Ph, R₃ = ethyl 10m R₂ =para-CH₃—Ph, R₃ = isobutyl 10n R₂ = para-CH₃—Ph, R₃ = H 10o R₂ =para-CH₃—Ph, R₃ = ^(t)butyl 10p R₂ = para-CH₃—Ph, R₃ = cyclopropyl 10qR₂ = Ph, R₃ = cyclopropyl

FIG. 7 is a synthetic route to library 16. Reagents and conditions: l. iNaH, THF, ii NaH, THF, iii NaOH, H₂O, iv HCl, H₂O. m. SOCl₂, benzene,reflux, 3 h. n. 10f, Et₃N, THF, 15 min. o. (±)-Ethyl 2-bromopropionate,K₂CO₃, CH₃CN, reflux, 12 h. p. NaOH, THF, reflux, 30 min. Scheme 1references the reaction scheme shown in FIG. 6. Library information isin Table 3 for library 16 or as follows:

Library 13 13a R₁ = methyl 13b R₁ = propyl Library 14 14a R₁ = methyl,racemic mix 14b R₁ = methyl, S-isomer 14c R₁ = methyl, R-isomer 14d R₁ =propyl, racemic mix 14e R₁ = propyl, S-isomer 14f R₁ = propyl, R-isomerLibrary 15 15a R₁ = methyl, racemic mix 15b R₁ = methyl, S-isomer 15c R₁= methyl, R-isomer 15d R₁ = propyl, racemic mix 15e R₁ = propyl,S-isomer 15f R₁ = propyl, R-isomer Library 16 16a R₁ = methyl, racemicmix 16b R₁ = methyl, S-isomer 16c R₁ = methyl, R-isomer 16d R₁ = propyl,racemic mix 16e R₁ = propyl, S-isomer 16f R₁ = propyl, R-isomer

FIG. 8 is a diagrams showing the predicted binding interactions ofPI-1833 in the b5 and b6 subunits of the 20S proteasome.

FIG. 9 is an illustration of the b5 and b6 subunits of the 20Sproteasome and interaction with PI-1833.

FIG. 10 is a diagram showing the lead compound PI-1840, entry 11ad, andits corresponding IC₅₀ value.

FIG. 11 is a graph showing the in vitro IC50 value for PI-1833 againstthe CT-L activity of purified 20S proteasome.

FIG. 12 is a graph showing the in vitro IC50 value for PI-1840 againstthe CT-L activity of purified 20S proteasome.

FIG. 13 is a graph showing the recovery of CT-L activity upon dialysisof the 20S proteasome-compound complexes after pre-incubation withPI-1833, PI-1840, and Bortezomib.

FIG. 14 is a graph showing PI-840 is more potent than PI-1833 atinhibiting CT-L activity in human breast cancer MDA-MB-468 cells.

FIG. 15 is a graph showing PI-1840 inhibits CT-L but not T-L or PGPHactivities within 10 min of MDA-MB-468 cells.

FIG. 16 is a blot showing PI-1840 is more potent than PI-1833 ataccumulating the proteasome substrates p27, Bax and IKB.

FIG. 17 is a blot showing the apoptotic potential of PI-1833 andPI-1840. Exponentially growing human breast cancer cells MDA-MB-468 andcolon cancer cells HCT-116 were treated with different concentrations ofPI-1833 or PI-1840 for 48 h or 24 h, followed by WB analysis for cleavedcaspase-3 and cleaved PARP.

FIG. 18 is a diagram showing the modification sites around PI-1833 forthe library synthesis.

FIG. 19 is a diagram showing the on-going synthetic modifications toPI-1833.

FIG. 20 is a diagram illustrating the synthesis of urea-modified PI-1833analogs. Reagents and conditions: a Et₃N, benzene, reflux, 2 h, 78%.

FIG. 21 is a synthetic route to for modifications to the backbonestructure. Reagents and conditions i) q. Et₃N, benzene, reflux, 12 h,78%, ii) r. Chloroacetyl chloride, Et₃N, THF, 15 min, 78%, s.para-Methylaniline, NaOAc, ethanol, reflux, 12 h, 73%, iii) f SOCl₂,benzene, reflux, 3 h, 95%, h. acetone, 30 min. i. toluene, reflux, 2 h.j. Isopropylamine, K₂CO₃, CH₃CN, reflux, 30 min. k. 10d, Et₃N, THF, 15min, 78%. Scheme 1 references the reaction scheme shown in FIG. 6.

FIGS. 22(A) and (B) are diagrams showing (A) the structures of PI-1833and PI-1840 identifying the heterocyclic oxadiazole moiety of thebackbone structure and (B) different heterocyclic moieties that mayreplace the oxadiazole moiety in PI-1833/PI-1840 class of compounds.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The terms “about” and “approximately” mean means nearly and in thecontext of a numerical value or range set forth means±15% of thenumerical

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., an antimalarial agent, etc.), “administration” and its variantsare each understood to include concurrent and sequential introduction ofthe compound or prodrug thereof and other agents.

As used herein, the term “cancer” or “cancerous” refer to or describethe physiological condition in mammals that is typically characterizedby unregulated cell growth, i.e., proliferative disorders. Examples ofsuch proliferative disorders include cancers such as carcinoma,lymphoma, blastoma, sarcoma, and leukemia, as well as other cancersdisclosed herein. More particular examples of such cancers includebreast cancer, prostate cancer, colon cancer, squamous cell cancer,small-cell lung cancer, non-small cell lung cancer, gastrointestinalcancer, pancreatic cancer, cervical cancer, ovarian cancer, livercancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer,endometrial carcinoma, kidney cancer, and thyroid cancer.

As used herein, “Ph” stands for phenyl.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician. In reference to malaria, an effective amount comprisesan amount sufficient to cause a reduction in the parasite load and/or todecrease the proliferation of the plasmodium or to prevent or delayother unwanted infection. In some embodiments, an effective amount is anamount sufficient to delay development. In some embodiments, aneffective amount is an amount sufficient to prevent or delay occurrenceand/or recurrence. An effective amount can be administered in one ormore doses.

As used herein, “treatment” refers to obtaining beneficial or desiredclinical results. Beneficial or desired clinical results include, butare not limited to, any one or more of: alleviation of one or moresymptoms, diminishment of extent of the disease, stabilization (i.e.,not worsening), preventing or delaying spread of the malaria, preventingor delaying occurrence or recurrence of malaria, delay or slowing ofdisease progression, amelioration of the malaria, and remission (whetherpartial or total). The methods of the invention contemplate any one ormore of these aspects of treatment.

A therapeutically effective amount of the therapeutic compound or apharmaceutically acceptable salt, hydrate, or solvate thereof refers tothat amount being administered which will relieve, to some extent, oneor more of the symptoms associated with the disorder being treated. Inreference to the treatment of a proliferative cellular disorder, atherapeutically effective amount refers to the amount which: (1) reducesthe size of a tumor, (2) inhibits (i.e. stopping or slowing to someextent) tumor metastasis, (3) inhibits (i.e. stopping or slowing to someextent) tumor growth, (4) inhibits (i.e. stopping or slowing to someextent) cellular proliferation, (5) inhibits (i.e. stopping or slowingto some extent) expression of any member of the E2F family and/or (6)inhibits (i.e. stopping or slowing to some extent) activity (e.g. DNAbinding activity) of any member of the E2F family.

The pharmaceutical compositions of the subject invention can beformulated according to known methods for preparing pharmaceuticallyuseful compositions. Furthermore, as used herein, the phrase“pharmaceutically acceptable carrier” means any of the standardpharmaceutically acceptable carriers. The pharmaceutically acceptablecarrier can include diluents, adjuvants, and vehicles, as well asimplant carriers, and inert, non-toxic solid or liquid fillers,diluents, or encapsulating material that does not react with the activeingredients of the invention. Examples include, but are not limited to,phosphate buffered saline, physiological saline, water, and emulsions,such as oil/water emulsions. The carrier can be a solvent or dispersingmedium containing, for example, ethanol, polyol (for example, glycerol,propylene glycol, liquid polyethylene glycol, and the like), suitablemixtures thereof, and vegetable oils. Formulations are described in anumber of sources that are well known and readily available to thoseskilled in the art. For example, Remington's Pharmaceutical Sciences(Martin E W [1995] Easton Pa., Mack Publishing Company, 19^(th) ed.)describes formulations which can be used in connection with the subjectinvention. Formulations suitable for parenteral administration include,for example, aqueous sterile injection solutions, which may containantioxidants, buffers, bacteriostats, and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and nonaqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze dried (lyophilized) conditionrequiring only the condition of the sterile liquid carrier, for example,water for injections, prior to use. Extemporaneous injection solutionsand suspensions may be prepared from sterile powder, granules, tablets,etc. It should be understood that in addition to the ingredientsparticularly mentioned above, the formulations of the subject inventioncan include other agents conventional in the art having regard to thetype of formulation in question. The pharmaceutical composition can beadapted for various forms of administration. Administration can becontinuous or at distinct intervals as can be determined by a personskilled in the art.

The therapeutic compound is administered and dosed in accordance withgood medical practice, taking into account the clinical condition of theindividual patient, the site and method of administration, scheduling ofadministration, patient age, sex, body weight, and other factors knownto medical practitioners.

Example 1

High throughput screening of a 50,000 compound library against CT-Lactivity resulted in the discovery of PI-1833, a non-covalent andrapidly reversible proteasome inhibitor. Analysis of PI-1833, depictedin FIG. 2, exhibited an in-vitro IC₅₀ value of 0.65±0.39 μM. Testing inwhole cell MDA-MB-468 (breast cancer cells) showed the IC₅₀ activity ofPI-1833 was IC₅₀=1.1 μM. The compound 1 has not previously been reportedas a proteasome inhibitor. PI-1833 was synthesized according to theprotocols shown in, FIG. 3 to confirm both the structure and in-vitrochymotrypsin-like (CT-L) activity of the compound. Starting fromN-Hydroxy-4-methyl-benzamidine 1, the right hand portion of the PI-1833(compound 4) was synthesized, which was then reacted with isopropylamine 5 to form the compound 6. The left hand portion of the molecule 11was synthesized from p-cresol 7 and bromoethylacetae 8. In the laststep, the two building blocks were combined to obtain the PI-1833(compound 12), in good yield.

The in-house synthesized materials and commercial samples wererigorously analyzed using ¹H NMR, ¹³C NMR, low resolution and formulaguided mass spectrometry. The NMR of PI-1833 showed a mixture ofrotamers about the amide bond (approximately 1:3 ratios). The in-housesynthesized PI-1833 confirmed the CT-L inhibitory activity and thestructure. The purity of the commercial and in-house synthesizedcompounds was also determined by HLPC (>95% HPLC purity, 30 min.methods) and LCMS. The whole cell activity (MBA-MD-468 breast cancercell line was used) of PI-1833 was determined as 1 μM.

Example 2

The synthesis of the first generation analogs of PI-1833 were undertakento understand the structural moieties important for activity and toevaluate SAR (structure activity relationship) data, which also confirmsPI-1833 as an authentic proteasome inhibitor.

Initial synthetic modifications included substitution of the methylgroups on ring A and ring B with small hydrophobic groups such as Cl,CF₃, F, isopropyl and bi-phenyl groups, seen in FIG. 4. The isopropylamide moiety was synthetically modified to isobutyl, methyl, ethyl andnaked amide (isopropyl group substituted with H). The synthesis of thesecompounds is summarized in FIG. 5.

The acetyl chloride building block library 5, seen in FIG. 6, wassynthesized from readily available phenol derivatives via theintermediates ester 3 and acid 4 using reported protocols. Theoxadiazole portion of the compound 1 was synthesized from readilyavailable nitrile building blocks 6. The nitrile building blocks werereacted with hydroxylamine hydrochloride and sodium carbonate at 70° C.in water to yield the hydroxyamidines 7 (Gezginci, et al.Antimycobacterial Activity of Substituted Isosteres of Pyridine- andPyrazinecarboxylic Acids. 2. J. Med. Chem. 2001, 44, 1560-1563), as seenin FIG. 6, condition g. The 2-substituted pyrimidine oxime wassynthesized from the corresponding ester (Ji, et al. Oxadiazolederivatives as nicotinic acetylcholine receptor subtype a4b2 positiveallosteric modulators and their preparation, composition and use for thetreatment of pain. 2010-US36213). The intermediate hydroxyamidinelibrary 7 was reacted with chloroacetyl chloride (condition h) toprovide the library 8 (Sindkhedkar, et al. Preparation of erythromycinmacrolides and ketolides having antimicrobial activity. 2007-IB2405),which was cyclized in refluxing toluene to provide the oxadiazoleportion of the pharmacophore 9. The library 9 was subsequently reactedwith different alkyl amines (isopropyl-, isobutyl-, methyl-, ethyl-,cyclopropyl- and tert-butyl-amines) to obtain the amine-building blocklibrary 10, seen in FIG. 6, condition j. Library 10 was generated with avariety of substituted alkyl and hetero-alkyl R² moieties and library 5with substituted/unsubstituted aromatic R¹ moieties. The two keybuilding block libraries 10 and 5 were then reacted in the presence oftriethylamine to provide the compound 1, library 11 and 12, seen in FIG.6, and Tables 1 and 2, in good yields. The route described was efficientand convenient for rapid synthesis and optimization of substitutedphenyl and the amide moieties. The final libraries were characterizedusing NMR, LC-MS, HRMS and the purity was >95% as determined by HPLC.The final compound library 11 and 12 showed 3:1 ratio of atropisomers(hindered rotation about the C—N bond) by ¹H NMR spectroscopy.

TABLE 1 Compound 1, synthetic analogs of library 11 and SAR.

Name R₁ R₂ IC₅₀ (μM) Chymotrypsin- like activity  1 SO1-143

 0.63 ± 0.35 (n = 39) 11a SO1-176

 1.08 ± 0.33 (n = 4) 11b SO1-171

 0.43 ± 0.12 (n = 4) 11c SO1-170

 2.53 ± 0.95 (n = 5) 11d SO1-169

0.857 ± 0.35 (n = 9) 11e SO2-002

 1.12 ± 0.33 (n = 5) 11f SO1-180

1.405 ± 0.185 (n = 2) 11g SO1-179

 1.07 ± 0.05 (n = 4) 11h SO1-181

 0.51 ± 0.16 (n = 6) 11i SO1-160

 0.45 ± 0.15 (n = 4) 11j SO2-011

 6.22 ± 1.11 (n = 2) 11k SO2-006

 8.47 ± 0.59 (n = 2) 11l SO2-010

15.11 ± 6.94 (n = 4) 11m SO1-172

 0.31 ± 0.08 (n = 4) 11n SO1-159

 0.97 ± 0.15 (n = 2) 11o SO2-058

>10 11p SO2-073

>10 11q SO2-045

>10 11r SO2-046

>10 11s SO2-030

 8.73 ± 3.05 (n = 4) 11t SO2-089

27.76 ± 20.83 (n = 5) 11u SO2-170

 0.98 ± 0.50 (n = 3) 11v SO2-171

10.12 ± 4.52 (n = 3) 11w SO2-075

3.747 ± 1.47 (n = 6) 11x SO2-076

0.239 ± 0.097 (n = 6) 11y SO2-069

 0.37 ± 0.046 (n = 4) 11z SO2-179

 4.00 ± 0.89 (n = 3) 11aa SO2-050

0.267 ± 0.05 (n = 6) 11ab SO2-103

0.099 ± 0.032 (n = 14) 11ac SO3-030

 3.12 ± 1.11 (n = 6) 11ad SO2-184

0.032 ± 0.00015 (n = 10) 11ae SO3-026

0.039 ± 0.011 (n = 7) 11af SO3-050

0.121 ± 0.040 (n = 3) 11ag SO3-051

0.428 ± 0.038 (n = 3) 11ah SO3-066

1.356 ± 0.184 (n = 3) 11ai SO3-080

0.436 ± 0.073 (n = 3) 11aj SO3-079

65.93 ± 33.68 (n = 3) 11ak SO3-089

0.140 ± 0.052 (n = 3) 11al SO3-074

0.032 ± 0.003 (n = 3) 11am SO3-057

0.105 ± 0.031 (n = 3) 11an SO3-054

0.107 ± 0.013 (n = 3) 11ao SO3-096

1.269 ± 0.226 (n = 3) 11ap SO3-126

NA 11aq SO2-068

>10 μM

TABLE 2 Synthetic analogs of Library 12 and SAR.

Name R₃ IC₅₀ (μM) Chymotrypsin- like activity  1 SO1-143 isopropyl   0.63 ± 0.35 (n = 39) 12a SO1-157 isobutyl    2.37 ± 0.40 (n = 2) 12bSO2-012 ethyl    8.98 ± 5.21 (n = 4) 12c SO1-184 methyl    29.9 ± 3.9 (n= 2) 12d SO2-007 H −62% @10 μM. 12e SO2-070 tert-butyl −108.42 ± 118.76%(n = 5) @ 10 μM 12f SO3-084 cyclopropyl  −8.36 ± 19.03% @ 10 μM

Library 16 was analyzed for racemic, R and S enantiomers, seen in FIG.7, by adding a methyl group adjacent to the phenoxy moiety in 1 tounderstand if this class of compounds shows chiral discrimination towardinhibition of the proteasome. A racemic mixture, and the R and S isomers(16a, 16b and 16c respectively, R¹=methyl, seen in Table 3, weresynthesized from a moderately potent compound 11x, and as we developeddetail SAR, the racemate and enantiomers (16c, 16d and 16e, R¹=propyl,Table 3) of the most potent compound 11ad were also synthesized tounderstand how the enantiomers influence the CT-L potency. Commerciallyavailable R and S 2-bromopropionic acid, FIG. 7, were reacted withpara-methylphenol and para-propylphenol to obtain intermediate acidlibrary 14 (Scheme 2). The acids 14 were converted to acid chlorides(harma, P. C.; Yadav, S.; Pahwa, R.; Kaushik, D.; Jain, S. Synthesis andevaluation of novel prodrugs of naproxen. Med. Chem. Res. 2011, 20,648-655; Yang, Q.; Olmsted, C.; Borhan, B. Absolute StereochemicalDetermination of Chiral Carboxylic Acids. Org. Lett. 2002, 4, 3423-3426;Allegretti, et al. 2-Arylpropionic CXC Chemokine Receptor 1 (CXCR1)Ligands as Novel Noncompetitive CXCL8 Inhibitors. J. Med. Chem. 2005,48, 4312-4331) 15 that was subsequently reacted with building block 10f(R³=isopropyl, R²=meta-pyridyl, seen in FIG. 6, to obtain library 16.The synthetic route depicted in FIG. 7 provided final compounds 16 withoverall retention of stereochemistry. The chiral purity of the librarymembers of 16 was determined by chiral HPLC (see the details insupporting information). The chiral purity of the S-isomer (16b, R¹=Me)was found to be 92% and R-isomer (16c, R¹=Me) was 98%. Similarly 16eS-isomer (R¹=propyl) and 16f R-isomer (R¹=propyl) showed 91% and 98%chiral purity respectively. The racemic compounds 16a and 16d, shown inFIG. 7, were obtained first reacting para-methylphenol andpara-propylphenol with ethyl 2-bromopropionate to give 13 which washydrolyzed using NaOH in refluxing THF to provide the racemicintermediates 14. The intermediates 14 were converted to acid chlorides15 and subsequently reacted with 10f to provide the required racemiccompounds (±)-16a and (±)-16d. Racemic compounds were also used forchiral HPLC method development (i.e. separate enantiomers using a chiralcolumn) and to assess the chiral purity of the individual R and Sisomers.

TABLE 3 CT-L activities and SAR of the library 16.

Name R₁ IC₅₀ (μM) CT-L 16a racemic mixture SO2-145

 0.38 ± 0.099 (n = 16) 16b S-isomer SO3-019

0.214 ± 0.053 (n = 7) 16c R-isomer SO3-065 (R Isomer)

 7.52 ± 2.13 (n = 7) 16d racemic mixture SO3-106

0.289 0.056 16e S-isomer SO3-110

0.075 0.029 16f R-isomer SO3-109

 2.18 ± 0.28

Modifications on the benzene rings with hydrophobic substituentsretained the activity. The methyl or trifluoromethyl group on the ring Aand hydrogen on the ring B improved the activity (from 700 nm to 300nm). The SAR data are summarized in the Table 4.

TABLE 4 Summary of SAR of modifications around rings A and B.

R₁ R₂ IC₅₀ (μM) Chymotrypsin- like activity PI-1833 (23) CH₃ CH₃ 0.716 ±0.27 (n = 14) 21 CF₃ CH₃  1.08 ± 0.33 (n = 4) 22 Cl CH₃  1.04 ± 0.05 (n= 2) 24 H CH₃  8.47 ± 0.59 (n = 2) 27 CH₃ CF₃  0.97 ± 0.15 (n = 2) 26 ClCF₃  1.41 ± 0.19 (n = 2) 25 CF₃ CF₃  2.05 ± 0.58 (n = 2) 28 H CF₃ 15.11± 6.94 (n = 4) 35 CH₃ Cl  0.45 ± 0.18 (n = 3) 34 CF₃ Cl  0.86 ± 0.35 (n= 9) 33 Cl Cl  1.07 ± 0.05 (n = 4) 32 H H  6.22 ± 1.11 (n = 2) 31 CH₃ H 0.32 ± 0.08 (n = 3) 29 CF₃ H  0.38 ± 0.09 (n = 3) 30 Cl H  0.51 ± 0.17(n = 5)

The structural components of PI-1833 suggest PI-1833 is a non covalentproteasome inhibitor. PI-1833 was docked to CT-L (β-5) subunit (Core B,Consortium for Functional Glycomics, La Jolla, Calif.) to identify andunderstand the medicinal chemistry of PI-1833 as a proteasome inhibitor.As seen in FIGS. 8 and 9, PI-1833 interacts with the proteasome atthreonine 1 and 21, glycine 47 and aspartic acid 114. The generatedanalogs of PI-1833 show SAR results suggesting efficacious interactionwith proteasomes. Further testing of the analoges show a series ofpotent (below 100 nM), non-covalent drug-like proteasome inhibitors weredeveloped from this class of compounds, seen in Table 5.

TABLE 5 PI-1833 and aromatic-ring-substituted analogs synthesized toidentify proteasome inhibitor compounds. Screening Results (% Whole cellName Inhibition @ IC₅₀ (μM) IC₅₀ (μM) Molecular Wt 10 μM) Chymo- Chymo-(Amt. Supplied mg) Chymotrypsin- trypsin- trypsin- Structure like likelike Comments

 0.63 ± 0.35 (n = 39) 1.1 (MDA- MB-468) In house synthesized 7871833HPLC > 99%

Primary 73% 1^(st) cherry pick 74% 2^(nd) cherry pick 67% 71% (n = 3) 0.65 ± 0.38 (n = 4) HPLC > 99%

 4.12 ± 0.09 (n = 2)

 5.13 ± 0.09 (n = 2)

 2.37 ± 0.40 (n = 2) HPLC = 99.07%

 0.97 ± 0.15 (n = 2) HPLC = 99.32%

 0.45 ± 0.15 (n = 4) HPLC = 99.62%

0.58 (FM) (Nov. 15, 2010) 0.857 ± 0.35 (n = 9) HPLC > 99%

 2.53 ± 0.95 (n = 5) HPLC = 98.90%

 0.43 ± 0.12 (n = 4) HPLC > 99%

0  0.31 ± 0.08 (n = 4) HPLC = 96.29%

 1.08 ± 0.33 (n = 4) HPLC = 99.87%

 1.07 ± 0.05 (n = 4) HPLC = 99.92%

1.405 ± 0.185 (n = 2) HPLC = 99.75%

 0.51 ± 0.16 (n = 6) HPLC = 99.92%

 29.9 ± 3.9 (n = 2) HPLC = 96.03%

 1.12 ± 0.33 (n = 5) HPLC = 99.61%

 8.47 ± 0.59 (n = 2) HPLC = 99.84%

−62.67% @ 10 μM Nov. 19, 2010 HPLC = 99.85%

15.11 ± 6.94 (n = 4) HPLC > 99%

 6.22 ± 1.11 (n = 2) HPLC = 94.37%

 8.98 ± 5.21 (n = 4) HPLC = 99.62%

 −8.75 ± 17.37 ND HPLC = 95.42%

44.03 ± 20.88 (n = 4) HPLC = 98.50%

 8.73 ± 3.05 (n = 4) HPLC > 99%

<70% ND HPLC = 99.6%

<70% ND HPLC = 99.25%

0.267 ± 0.05 (n = 6) HPLC = 95.49%

27.30 35.35 33.80 6.37 HPLC = 99.46%

<70% ND HPLC = 94.51%

ND HPLC = 97.95%

3.747 ± 1.47 (n = 6) HPLC = 95.31%

 0.22 ± 0.084 (n = 9) HPLC = 99.43%

 −53.02 ± 23.42 (n = 4) HPLC > 99%

 −62.02 ± 26.32 (n = 4) HPLC = 99.81%

−108.42 ± 118.76 (n = 5) HPLC = 97.73%

   27.76 ± 20.83 (n = 5) HPLC > 99%

   31.39 ± 11.20 (n = 4) HPLC = 97.51%

0.099 ± 0.032 (n = 14) HPLC = 94.88%

−174.75 ± 134.18 (n = 5) ND HPLC = 96.35%

   95.72 ± 0.88  0.37 ± 0.046 (n = 4) HPLC = 97.29%

   81.54 ± 2.77  5.67 ± 0.96 (n = 4) HPLC = 96.59%

92.43 ± 0.82 0.92 ± 0.21 (n = 4) HPLC = 99.77%

   92.93 ± 1.70  0.38 ± 0.099 (n = 16)

   80.38 ± 3.04 12.52 ± 2.96 (n = 4)

 −72.66 ± 44.80 (n = 6)    9.54 ± 10.89 (n = 5)

−149.24 ± 157.49 (n = 5)

   70.56 ± 5.09  4.00 ± 0.89

   78.37 ± 6.33  0.98 ± 0.50 (n = 3)

 −5.85 ± 23.45 10.12 ± 4.52 (n = 3)

   92.31 ± 2.19 0.032 ± 0.00015 (n = 10) HPLC = 96.36%

 0.14 ± 0.003 (n = 4) HPLC = 100%

0.039 ± 0.011 (n = 7) HPLC = 97.51%

0.379 ± 0.063 (n = 3)

 3.12 ± 1.11 (n = 6) HPLC = 97.50%

0.214 ± 0.053 (n = 7) S isomer

 7.52 ± 2.13 (n = 7) R isomer

0.121 ± 0.040 (n = 3) HPLC = 96.51%

0.428 ± 0.038 (n = 3)

0.107 ± 0.013 (n = 3) HPLC = 97.97%

0.105 ± 0.031 (n = 3) HPLC = 97.57%

0.032 ± 0.003 (n = 3) HPLC = 97.18%

1.356 ± 0.184 (n = 3) HPLC = 97.00%

65.93 ± 33.68 (n = 3)

0.436 ± 0.073 (n = 3) HPLC = 99.1%

 −8.36 ± 19.03 HPLC = 94.77%

0.140 ± 0.052 (n = 3) HPLC = 100%

1.269 ± 0.226 (n = 3) HPLC = 97.92%

(2.389) (1.986) R isomer

(0.0750) (0.02919) S isomer

(0.2893) (0.0563) Racemic mixture

The phenyl rings in compound 1 were modified (i.e. library 11), as seenin FIG. 6 and Table 1. Changing the para-methyl in R¹ and R² totrifluoromethyl (11c), seen in Table 1, Entry 4, or chlorine (11g), seenin Table 1, Entry 8, showed inhibitory activities with IC₅₀ 2.53 and1.07 μM respectively. Similarly, compounds 11a, 11d, 11e, 11f, 11i and11n with small hydrophobic groups such as CF₃, methyl or Cl in thepara-positions of R¹ and R² rings retained the in vitro CT-L inhibitoryactivities, seen in Table 1, Entries 2, 4-8, 10 and 15, possessed IC₅₀values around 1 μM. Compounds 11b, 11h and 11m, seen in Table 1, Entries3, 9 and 14, with an unsubstituted phenyl ring as R² showed slightlyimproved IC₅₀ values around 0.3 to 0.5 μM indicating para-substitutionin the R² phenyl is not required for activity. However compound 11j withboth unsubstituted phenyl rings resulted in 10 fold loss of CT-Lactivity, seen in Table 1, Entry 11, having an IC₅₀ value of 6.22 μM.Removal of the R¹ para-methyl group as in compounds 11k and 11l, seen inTable 1, Entries 12 and 13, also led to 13 and 25-fold loss of activity(IC₅₀ 8.4 and 15 μM respectively). The loss of in vitro potency ofcompounds 11j, 11k and 11l suggest that para-substitution in R¹ phenylis important, and in some cases vital, to maintain CT-L proteasomeactivity. Changing the R¹ para-methyl to meta- or ortho-position as incompounds 11o and 11p, seen in Table 1, Entries 16 and 17, indicatedloss of in vitro activity further suggesting that R¹ para-substitutionis important for CT-L proteasome activity. Overall, the SAR indicatedthat the para-methyl group in R¹ together with the isopropyl amide in 1were important to maintain the CT-L proteasome activity and loss ofactivity was consistently observed with unsubstituted R¹ aromatic rings.

Moieties at R¹ were then selected at the para-position (i.e. parasubstituted 6-bromonapthyl, biphenyl, OH, COOH, CH₃, ethyl, propyl,butyl) and unsubstituted aromatic R² rings (phenyl, pyridyl [ortho-meta-and para-], pyrimidine and pyrazine) for further syntheticmodifications, as seen in Table 1, Library 11. The best in vitro CT-Linhibitory activity was demonstrated by compounds 11ad and 11ae, seen inTable 1, having IC₅₀ values of 32 and 39 nM respectively, that possesseda propyl or butyl group in the para-position of the R¹ phenyl ring andmeta-pyridyl as R². The 20-fold improved activity of 11ad and 11aedemonstrated the key functional groups such as para-propyl orpara-butyl, isopropylamide and the 3-pyridyl groups of the oxadiazolepharmacophore are important for CT-L proteasome inhibitory activity. Thesignificantly improved in vitro potency of 11ad and 11ae were achievedby systematically changing the R¹ and R² moieties. Initially, compound11x, seen in Table 1, Entry 25, was observed to have an IC₅₀ value of0.239±0.09 μM with para-methylphenyl as R¹ and 3-pyridyl as R² thatshowed 2.5 fold improved CT-L activity compared to the hit 1. Similarly,11aa, seen in Table 1, Entry 28, with an IC₅₀ value of 0.26±0.05 μM,with para-ethylphenyl as R¹ and unsubstituted phenyl group as R² showed2 fold improved activity. The library member 11ab (combined features of11x and 11aa) with para-ethylphenyl as R¹ and 3-pyridyl as R² showed6-fold improved in vitro activity, as seen in Table 1, Entry 29, with anIC₅₀ value of 0.099±0.03 μM, and demonstrated the additive features of11x and 11aa led to improvement in CT-L inhibitory activity.Interestingly, loss of CT-L activity observed with 11ac, Table 1, Entry30, having an IC₅₀ value of 3.12±1.11 μM with an unsubstituted R¹ ringfurther highlighted the importance of para-substituted R¹ ring in 1 tomaintain the CT-L activity. We found compound 11w, Table 1, Entry 24,IC₅₀=3.74±1.47 μM, with 2-pyridyl as R² was less active, while 11y,Table 1, Entry 26, with an IC₅₀ value of 0.37±0.04 μM with para-pyridylmoiety was more tolerated for CT-L activity. The compound 11z with apara-methyl substituted pyridyl as R¹ failed to retain the activityprobably due to the H-bond acceptor (pyridyl) group.

With promising SAR data from the parent compound and aromaticsubstitutions, the compound 11ab was further modified to obtain the mostpotent analogs 11ad and 11ae. The hydrophobic ethyl group in 11ab wasfurther extended to propyl (11ad), butyl (11ae), pentyl (11af), hexyl(11ag) and cyclohexyl (11ah) and as the length of the hydrophobic chainincreased, the CT-L inhibitory activity was decreased, seen in Table 4,Entries 31-35, IC₅₀ changed from 32 nM to 1.3 μM. SAR studies on PI-1840(compound 11ad), seen in FIG. 10, exhibited a 20-fold more potentanalog, seen in FIGS. 11 and 12. Testing of compound PI-1840 and PI-1833showed both compounds are non-covalent and rapidly reversible proteasomeinhibitors, as seen in FIG. 13. In vitro testing of both PI-1833 andPI-1840 showed PI-1840 is more potent at inhibiting CT-L activity inhuman breast cancer, seen in FIG. 14, and acts through CT-L but not T-Lor PGPH activities within 10 min of administration, seen in FIG. 15.Western blots were performed to analyze the cellular proteins todetermine the pathway of action, and it was observed that PI-1840 ismore potent at accumulating the proteasome substrates p27, Bax and IKB,seen in FIG. 16, and acts through efficiently inducing apoptosis, asseen in FIG. 17. The effects of PI-1840 are not restricted to breastcancer, as seen in Table 6.

TABLE 6 Exponentially growing different cancer cells with differentgenetic background or normal/immortalized breast cells treated withdifferent concentrations of PI-1840 for 72 h or 96 h, followed by MTTassay to measure the tumor cell proliferation and viability. GeneticCancer Cell line(s) background 72 h 96 h Breast MDA-MB-468 WT K-Ras,25.45 ± 5.83 11.6 mut p53 MDA-MB-231 mut K-Ras 132.63 ± 21.57 105.5Colon HCT-116 mut K-Ras,  40.93 ± 15.80 35.27 WT p53 HCT-116-p53^(−/−)mut K-Ras,  45.93 ± 19.90 31.06 p53^(−/−) HCT-116-HKH2 K-Ras^(−/−),43.02 ± 9.73 12.83 WT p53 Prostate DU-145 Bax^(−/−) 122.93 ± 25.19 158.7LNCaP Bax^(+/+) 48.95 ± 6.81 17.25 PC3 92.67 62.51 Multiple RPMI-8226 35.93 ± 11.15 34.74 myeloma Pancreatic Colo357 N/A 95.65 Kidney RX7-397N/A 56.89 MCF-10A normal/ 63.07 ± 7.06 N/A immortalized

Compounds 11ad and 11ae displayed the best CT-L inhibitory activitieswith IC₅₀ values 32 nM and 39 nM respectively. These modifications werecritical to understand the SAR around the R¹ binding region of theproteasome. Compounds 11af, 11ag and 11ah with para-pentyl, para-hexyland para-cyclohexyl respectively showed 4-, 13- and 40-fold loss of CT-Lactivity, seen in Table 1, compared to 11ad or 11ae indicating longerchain hydrophobic substituents are less tolerated in the R¹ bindingregion of the CT-L domain. Compounds 11q and 11r that possessed largephenyl and Br-naphthyl as para-R¹ groups respectively, further indicatedthat large R¹ groups lead to poor CT-L inhibitory activity, Table 1,Entries 18, 19, <70% @ 10 μM. In contrast, replacement of methyl bysmall hydrophobic fluorine, Table 1, Entry 20, 11s, also led to poorCT-L inhibitory activity. The 20-fold loss of CT-L inhibitory activityof 11s with fluorine compared to 11b (Entry 3) is not surprising sincefluorine is isosteric to hydrogen and as described previously we havealready observed the detrimental effects of unsubstituted R¹ rings incompounds 11k, 11l and 11ac, seen in Table 1, toward the CT-L inhibitoryactivity. The hydrophilic COOH and OH groups in the para-position of theR¹ as in compounds 11t and 11v respectively also failed to maintain theCT-L inhibitory activity (IC₅₀=27 and 10 μM respectively) indicatingH-bond acceptor/donor moieties are not desirable as R¹ substituents.However compound 11u with para-hydroxyphenyl as R¹ and meta-pyridyl asR² showed an IC₅₀ value around 1 μM (Entry 22) and comparison of invitro CT-L inhibitory activities of 11u and 11v, Table 1, Entries 22 and23, with para-hydroxyphenyl as R¹ highlight the importance of thepara-pyridyl group for CT-L activity in this class of compounds.

Example 3

To further analyze Structure Activity Relationship (SAR) studies ofPI-1833, synthetic modifications were carried out to the compound'sbackbone structure, as shown in the FIG. 18. To see the effect ofisopropyl group on the CT-L activity, the isopropyl group was changed tomethyl, ethyl, isobutyl and hydrogen by using the route depicted in FIG.3.

The acetyl chloride building block library 5, seen in FIG. 6, wassynthesized from readily available phenol derivatives via theintermediates ester 3 and acid 4 using reported protocols. Theoxadiazole portion of the compound 1 was synthesized from readilyavailable nitrile building blocks 6. The nitrile building blocks werereacted with hydroxylamine hydrochloride and sodium carbonate at 70° C.in water to yield the hydroxyamidines 7 (Gezginci, et al.Antimycobacterial Activity of Substituted Isosteres of Pyridine- andPyrazinecarboxylic Acids. 2. J. Med. Chem. 2001, 44, 1560-1563), seen inFIG. 6, condition g. The 2-substituted pyrimidine oxime was synthesizedfrom the corresponding ester (Ji, J.; Lee, C.-L.; Sippy, K. B.; Li, T.;Gopalakrishnan, M. Oxadiazole derivatives as nicotinic acetylcholinereceptor subtype a4b2 positive allosteric modulators and theirpreparation, composition and use for the treatment of pain. 2010-US362132010138600, 20100526, 2010). The intermediate hydroxyamidine library 7was reacted with chloroacetyl chloride (condition h) to provide thelibrary 8 (Sindkhedkar, et al. Preparation of erythromycin macrolidesand ketolides having antimicrobial activity. 2007-IB2405 2008023248,20070822, 2008), which was cyclized in refluxing toluene to provide theoxadiazole portion of the pharmacophore 9. The library 9 wassubsequently reacted with different alkyl amines (isopropyl-, isobutyl-,methyl-. ethyl-, cyclopropyl- and tert-butyl-amines) to obtain theamine-building block library 10 (condition j). For the synthesis of 10n(R³═H), compound 9a (R²=para-tolyl) was first reacted with phthalimidein the presence of potassium carbonate in refluxing acetonitrile,followed by reaction with hydrazine to obtain the compound 10n in highyield. Library 10 was generated with a variety of substituted alkyl andhetero-alkyl R² moieties and library 5 with substituted/unsubstitutedaromatic R¹ moieties, seen in FIG. 6. Modifications to the two keybuilding block libraries 10 and 5 were then reacted in the presence oftriethylamine to provide the compound 1, library 11 and 12, seen in FIG.6, and Tables 1 and 2, in good yields. The route described was efficientand convenient for rapid synthesis and optimization of substitutedphenyl and the amide moieties. The final libraries 11, 12 and compound 1were characterized using NMR, LC-MS, HRMS and the purity was >95% asdetermined by HPLC. The final compound library 11 and 12 (includingcompound 1) showed 3:1 ratio of atropisomers (hindered rotation aboutthe C—N bond) by ¹H NMR spectroscopy (see the experimental section).

When the isopropyl group in PI-1833 was changed to isobutyl (36), ethyl(37), methyl (38) or hydrogen (39), the loss of CT-L proteasome activitywas observed. From these modifications, isopropyl group appears to playa key role on the CT-L proteasome activity. The results for thesemodifications are summarized in Table 7.

TABLE 7 Inhibition against 20S CT-L proteasome activity.

R₃ IC₅₀ (μM) CT-L 12 isopropyl 0.716 ± 0.27 (n = 14) 36 isobutyl 2.37 ±0.40 (n = 2) 37 CH₂CH₃ 8.98 ± 5.21 (n = 4) 38 CH₃ 29.9 ± 3.9  (n = 2) 39H ND

Additional replacement of the isopropyl group with tert-butyl orcyclopropyl moieties also showed diminished CT-L activities of thesecompounds and confirmed the isopropyl group is best tolerated forinhibitory activity, as seen Table 2. The isobutyl amide 12a and ethylamide 12b, seen in Table 2, Entries 46 and 47, showed 3- and 14-foldloss of activity (IC₅₀ 2.37 and 8.8 μM) respectively compared to 1, andmethyl, H, cyclopropyl and tert-butyl as R³ groups were detrimental forCT-L activity at 10 M (<70% inhibition @ 10 μM, 12c-12f). The ¹H NMR ofthe compound 1 with isopropyl group indicated approximately 3:1 ratio ofatropisomers (isomers that exist due to the hindered rotation about thecarbon-nitrogen bond). We observed similar ratio of atropisomers with12b and 12c with ethyl (2:1), methyl (2:1) respectively. Compound 12dwith unsubstituted amide, seen in Table 2. Entry 49, R³═H, 12e withbulky tert-butyl group, Table 2, Entry 50, R³=^(t)Bu, and 12f withcyclopropyl group (Entry 51, R³=Cyclopropyl) did not show atropisomersby ¹H NMR.

Synthetic modifications performed on the backbone focused on an ureamoiety or oxygen, as shown in FIG. 19, modified to determine thestringency of the backbone. Reacting the isocyante with the intermediate19 provided the urea 43 as depicted in FIG. 20. Oxygen was changed tocarbon to understand the interaction of the ether moiety in PI-1833 withThr-1 as postulated by modeling, seen in FIGS. 8 and 9. The synthesis ofthe corresponding compound is shown in FIG. 5. When the ether moiety inPI-1833 was replaced with carbon (compound 41), CT-L the activity wasdiminished. This may be due to the loss of interactions between theoxygen and Thr-1 as predicted by modeling. Incorporation of a ureamoiety in compound 43 also resulted in loss of CT-L activity. Resultsare summarized in Table 8.

The chemical space between the amide moiety and A and B rings ofcompound 1 were modified, as seen in FIG. 18. A urea moiety wasintroduced to assess the SAR. To install the urea moiety, intermediate10d, seen in FIGS. 6 and 21, was reacted with commercially availableisocyanate 17, and under these conditions urea 18 was obtained in goodyield, seen in FIG. 21, condition q. The ether moiety (H-bond acceptor)in 1 was then replaced with NH(H-bond acceptor/donor) group. The amine10d, seen in FIG. 6, was reacted with chloroacetyl chloride in thepresence of triethylamine in THF at room temperature and then coupledwith para-methylaniline using sodium acetate in refluxing ethanol toobtain 20, seen in FIG. 21, condition r and s, also in good yield. Theether oxygen moiety was also replaced by a methylene group using3-(4-(trifluoromethyl)phenyl)propanoic acid (21a) as the startingcompound. The phenylpropanoic acid 21a, seen in FIG. 21, was convertedto the corresponding acid chloride 22a and coupled with 10d to providecompound 23a, as seen in FIG. 21. The compound 23b with bulky sgroup wassynthesized following the route in FIG. 21 from benzofuran-2-carboxylicacid (21b) via the acid chloride 22b and subsequent coupling with 10d.Analysis of ¹H NMR spectroscopy of the compound 23b with bulkybenzofuran moiety as expected prevented hindered rotation about thecarbon-amide bond and generation of atropisomers. The intermediate 10dwas chosen for synthesis of compounds 18, 20 23a and 23b since our earlySAR indicated unsubstituted B ring retained in vitro CT-L potencytogether with para-CH₃ or para-CF₃ groups on the A ring.

The exciting findings related to compounds 11ad and 11ae promptedinvestigation of the SAR around para-propyl/butyl hydrophobic moietiesand synthetic modifications around the spacer between the R¹ and theamide moiety. The para-position of the R¹ moiety was modified bysynthesizing final compounds with branched hydrophobic moieties such asisopropyl, ^(t)butyl and isobutyl as in 11ai, 11aj and 11akrespectively, seen in Table 1. All 3 compounds failed to improve theCT-L activity compared to 11ad or 11ae, and compound 11aj withpara-tert-butyl group led to >35-fold loss of CT-L activity indicatingbranched hydrophobic groups are not tolerated in the R¹ binding region.

The para-propylphenyl or para-butylphenyl moieties were retained as R¹and changed the meta-pyridyl (R² group) to pyrimidine, Table 1, 11al,11ao, pyrazine (11am, 11an), and these changes did not lead to compoundswith improved CT-L inhibitory activity. Interestingly, 11al with5-pyrimidine (with both nitrogens in a meta-position) retained thein-vitro potency (IC₅₀=32 nM), whereas 2-pyrimidine 11ao (both nitrogensin an ortho-position) showed 40-fold loss of activity (IC₅₀=1.26 μM)indicating meta-nitrogen aromatic moiety is important for maintainingthe in vitro potency in the binding region. In contrast compounds 11amand 11an with pyrazine (which possess one meta-positioned nitrogen) onlyshowed a 3-fold loss of activity.

TABLE 8 Inhibition against 20S CT-L proteasome activity. Compound IC₅₀(μM) CT-L

15.70

ND

Further testing of the analoges show a series of potent (below 100 nM),non-covalent drug-like proteasome inhibitors were developed from thisclass of compounds, seen in Table 9.

TABLE 9 Compound backbone-substituted analogs synthesized to identifyproteasome inhibitor compounds. Screening Results (% Inhibition Wholecell Name Molecular Wt @ 10 μM) IC₅₀ (μM) IC₅₀ (μM) (Amt. Supplied mg)Chymotrypsin- Chymotrypsin- Chymotrypsin- Structure like like likeComments

HPLC = 95.42%

15.70 HPLC = 98.50%

−62.67% @ 10 μM Nov. 19, 2010 HPLC = 99.85%

   9.97% @ 10 μM 29.9 ± 3.9 (n = 2) HPLC = 96.03%

2.37 ± 0.40 (n = 2) HPLC = 99.07%

The synthetic modifications also provided compounds with a stereogeniccenter next to the ether moiety (by substituting one of the hydrogenswith methyl) as described in the synthesis of library 16, seen in Table3 and FIG. 8. We chose compound 11x, seen in Table 1, Entry 25, at anearly stage of this study to derive chiral and racemic compounds. As wedeveloped SAR, we introduced a stereogenic center to our most potentcompound 11ad, seen in Table 1. Hence the respective chiral and racemiccompounds, seen in Table 2, library 16, were derived from 11x and 11ad,the S and R enantiomers along with their racemic compounds weresynthesized as described in FIG. 7, to investigate against the CT-Lproteasome activity. The racemic 16a with para-methylphenyl as R¹ and3-pyridyl as R², seen in Table 3, Entry 52, displayed an IC₅₀ value of0.318 μM. While the S-enantiomer 16b was potent, seen in Table 3, Entry53, with an IC₅₀ value of 0.214 μM, the R-enantiomer 16c showed 35-foldloss of activity. Similarly, S-enantiomer 16e was 40-fold more potentthan the R-enantiomer 16f (with para-propylphenyl as R¹ and meta-pyridylas R²) and the racemic mixture 16d showed an IC₅₀ value of 0.289 μM. Themarked differences in the IC₅₀ values of S- and R-isomers, seen in Table3, Entries 16b vs 16C and 16e vs 16f, highlight that these compounds arechirally discriminated in inhibiting the 20S proteasome. Thisobservation is critical for our on-going studies and identifying potentproteasome inhibitors, since less potent R-isomer can be used as acontrol for cell biology and animal studies.

The spacer groups in 1 were simultaneously modified using the syntheticroutes in the FIG. 21. First, replacement of the ether-oxygen bymethylene showed loss of CT-L activity, seen in Table 10, Entry 58,IC₅₀=15 μM. Furthermore, substituting the amide group by urea as in 18,seen in Table 10, Entry 59, IC₅₀=>10 μM, also led to loss of activity.Replacement of the ether (H-bond acceptor) with NH(H-bonddonor/acceptor) also decreased the in vitro activity (Entry 60, 20,IC₅₀=5.67 μM). These synthetic modifications confirmed that the ethermoiety as H-bond acceptor is critical for focused library synthesis andimproving CT-L inhibitory activity. Extending the spacer between theamide and the oxadiazole by one carbon as shown in 24, seen in Table 10,Entry 61, 31% @ 10 μM, was detrimental for CT-L inhibitory activity,probably due to the increased flexibility of the structure.

TABLE 10 Modifications of the spacer between the amide R¹ phenyl and R²phenyl and CT-L activities. Compound Entry # Structure and ID Name IC₅₀(μM) CT-L 58

SO2-027 15.70 59

SO2-024 >10 60

SO2-090    5.67 ± 0.96 (n = 4) 61

SO2-091 31.39% ± 11.20 (n = 4) @ 10 μM 62

SO3-029 0.379 ± 0.063 (n = 3)

Example 4

Analysis of the Structure Activity Relationship (SAR) studies ofPI-1833, PI-1840 and the remaining analogs against the proteasome showedsynthetic modifications may be carried out on the oxadiazole moiety ofthe backbone. A listing of heterocyclic moieties to replace oxadiazolepharmacophore in PI-1833/PI-1840 class of compounds are seen in FIGS.22(A) and (B).

Example 5

All reagents were purchased from commercial suppliers and used withoutfurther purification. Melting points were determined using a Barnsteadinternational melting point apparatus and remain uncorrected. Proton NMRspectra were recorded on an Agilent-Varian Mercury 400 MHz spectrometerwith CDCl₃ or DMSO-d₆ as the solvent. Carbon (¹³C) NMR spectra arerecorded at 100 MHz. All coupling constants are measured in Hertz (Hz)and the chemical shifts (δ_(H) and δ_(C)) are quoted in parts permillion (ppm) relative to TMS (δ 0), which was used as the internalstandard. High resolution mass spectroscopy was carried out on anAgilent 6210 LC/MS (ESI-TOF). Low resolution mass spectroscopy (LRMS)was performed on an Agilent single quad G1956A (Chemistry Department,University of South Florida). Microwave reactions were performed in CEM908005 model and Biotage initiator 8 machines. HPLC analysis wasperformed using a JASCO HPLC system equipped with a PU-2089 Plusquaternary gradient pump and a UV-2075 Plus UV-VIS detector, using anAlltech Kromasil C-18 column (150×4.6 mm, 5 μm) and Agilent EclipseXDB-C18 (150×4.6 mm, 5 μm). Chiral HPLC analysis was performed using aJASCO HPLC system equipped with a PU-2089 Plus quaternary gradient pumpand a UV-2075 Plus UV-VIS detector, using OD column 9cellulose tris(3,5-dimethylphenylcarbamate) coated on 10 μm silica gel. Melting pointswere recorded on an Optimelt automated melting point system (StanfordResearch Systems). Thin layer chromatography was performed using silicagel 60 F254 plates (Fisher), with observation under UV when necessary.Anhydrous solvents (acetonitrile, dimethylformamide, ethanol,isopropanol, methanol and tetrahydrofuran) were used as purchased fromAldrich. Burdick and Jackson HPLC grade solvents (methanol, acetonitrileand water) were purchased from VWR for HPLC and high resolution massanalysis. HPLC grade TFA was purchased from Fisher.

SO1-133 (3a)

Ethyl 2-(p-tolyloxy)acetate (SO1-133): (3a): To a solution of p-cresol(3.0 g, 28 mmol) in acetone (30 ml) was added potassium carbonate (11.6g, 84 mmol) and ethyl bromoacetate (5.6 g, 33 mmol) and the mixture wasrefluxed overnight. Potassium carbonate was filtered and acetone wasevaporated to give the pure compound as a white solid (4.2 g, 90%).

¹H NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.6 Hz,2H), 4.59 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 2.28 (s, 3H), 1.29 (t, J=7.1Hz, 3H).

SO1-148 (3b)

Ethyl 2-(4-trifluoromethyl)phenoxy)acetate (SO1-148) (3b): This compoundwas synthesized using the same protocol for SO1-133 3a except using4-(trifluoromethyl)phenol (2.43 g, 15.00 mmol), ethyl bromoacetate (3.01g, 18.00 mmol) and potassium carbonate (10.35 g, 75.00 mmol). SO1-148 3bwas isolated as a white solid. (3.61 g, 97%). ¹H NMR (400 MHz, DMSO) δ6.78 (d, J=8.4 Hz, 2H), 6.26 (d, J=8.5 Hz, 2H), 3.98 (d, J=1.2 Hz, 2H),3.44 (q, J=7.1 Hz, 2H), 0.47 (q, J=7.1 Hz, 3H),

SO1-173 (3d)

Ethyl 2-(4-chloromethyl)phenoxy)acetate (SO1-173) (3d): This compoundwas synthesized using the same protocol for SO1-133 3a except using4-(chloromethyl)phenol (2.70 g, 21.00 mmol), ethyl bromoacetate (4.21 g,25.20 mmol) and potassium carbonate (14.49 g, 105.00 mmol). SO1-173 3dwas isolated as a white solid. (4.18 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ7.24 (d, J=8.5 Hz, 2H), 6.84 (dd, J=9.1, 0.5 Hz, 2H), 4.59 (s, 2H), 4.26(q, J=7.2, 1H), 1.29 (t, J=7.2, 1H).

SO2-037 (3e)

Ethyl 2-(biphenyl-4-yloxy)acetate (SO2-037) (3e): To a solution ofbiphenyl-4-ol (2.00 g, 11.75 mmol), in DMF (20 ml) was added ethylbromoacetate (2.35 g, 14.10 mmol) and potassium carbonate (8.11 g, 58.75mmol) and stirred at rt overnight. The solution was diluted with DCM (20ml) and washed with water (5×20 ml). Organic layer was dried andevaporated to provide SO2-037 3e as a white solid. (2.76 g, 90%). ¹H NMR(400 MHz, CDCl₃) δ 7.58-7.47 (m, 4H), 7.41 (t, J=7.6 Hz, 2H), 7.31 (t,J=7.3 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.65 (s, 2H), 4.28 (q, J=7.1 Hz,2H), 1.31 (t, J=7.1 Hz, 3H).

SO2-039 (3g)

Ethyl 2-(6-bromonapthalen-2-yloxy)acetate (SO2-039) (3g): This compoundwas synthesized using the same protocol for SO2-037 3e except using6-bromonapthalen-2-ol (1.06 g, 4.75 mmol), ethyl bromoacetate (0.95 g,5.70 mmol) and potassium carbonate (3.28 g, 23.75 mmol). SO2-039 wasisolated as a white solid. (1.27 g, 82%). ¹H NMR (400 MHz, CDCl₃) δ 7.92(d, J=1.7 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.50(dd, J=8.7, 1.9 Hz, 1H), 7.34-7.14 (m, 1H), 7.03 (d, J=2.4 Hz, 1H), 4.29(q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).

SO2-049 (3h)

Ethyl 2-(m-tolyloxy)acetate (SO2-049) (3h): This compound wassynthesized using the same protocol for SO2-037 3e except using m-cresol(1.00 g, 9.25 mmol), in DMF (20 ml) was added ethyl bromoacetate (1.85g, 11.10 mmol) and potassium carbonate (8.11 g, 46.25 mmol). SO2-049 3hwas isolated as a yellow-brown solid. (1.67 g, 93%). ¹H NMR (400 MHz,CDCl₃) δ 7.16 (t, J=7.9 Hz, 1H), 6.81 (dd, J=4.4, 3.7 Hz, 1H), 6.75-6.58(m, 2H), 4.60 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 2.32 (s, 3H), 1.29 (t,J=7.1 Hz, 3H).

SO2-038 (3j)

Ethyl 2-(4-ethylphenoxy)acetate (SO2-038) (3j): This compound wassynthesized using the same protocol for SO1-133 3a except using4-ethylphenol (0.75 g, 6.14 mmol), ethyl bromoacetate (1.23 g, 7.37mmol) and potassium carbonate (4.24 g, 30.70 mmol). SO2-038 3j wasisolated as a viscous yellow liquid. (1.06 g, 85%).

¹H NMR (400 MHz, CDCl₃) δ 7.12 (dd, J=8.2, 0.6 Hz, 2H), 6.84 (d, J=8.7Hz, 2H), 4.60 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 2.58 (t, J=7.6 Hz, 3H),1.30 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.6 Hz, 3H).

SO2-180 (3k)

tert-Butyl 2-(4-propylphenoxy)acetate (SO2-180) (3k): A solution4-propylphenol (500 mg, 3.67 mmol), tert-butyl 2-bromoacetate (716 mg,3.67 mmol) and potassium carbonate (2.55 g, 18.5 mmol) in DMF (10 ml)were heated at 80° C. for 14 h. The solution was diluted with water (20ml) and extracted with dichloromethane (2×20 ml). Organic phase waswashed with water (5×20 ml), dried (MgSO₄) and evaporated. The residuewas purified by column chromatography (EtOAc:hexane gradient elution) toobtain SO2-180 3k as a viscous liquid (753 mg, 82%).

¹H NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.7 Hz, 2H), 6.81 (d, J=8.7 Hz,2H), 4.48 (s, 2H), 2.51 (t, J=7.4 Hz, 2H), 1.66-1.55 (m, 2H), 1.48 (s,9H), 0.91 (t, J=7.3 Hz, 3H).

SO3-017 (3l)

Tert-butyl 2-(4-butylphenoxy)acetate (SO3-017) (3l): This compound wassynthesized using the same protocol for SO2-180 3k except using4-butylphenol (515 mg, 3.43 mmol), tert-butyl 2-bromoacetate (669 mg,3.43 mmol) and potassium carbonate (2.37 g, 17.15 mmol) The compoundSO3-017 31 was isolated as a yellow viscous liquid. (698 mg, 77%).

¹H NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.7 Hz,2H), 4.48 (s, 2H), 2.54 (t, J=7.7 Hz, 2H), 1.61-1.48 (m, 2H), 1.38-1.25(m, 2H), 0.91 (t, J=7.3 Hz, 3H).

SO3-043 (3m)

Tert-butyl 2-(4-pentylphenoxy)acetate (SO3-043) (3m): This compound wassynthesized using the same protocol for SO2-180 3k except using4-pentylphenol (500 mg, 3.04 mmol), tert-butyl 2-bromoacetate (593 mg,3.04 mmol) and potassium carbonate (2.10 g, 15.2 mmol) The compoundSO3-043 3m was isolated as a yellow viscous liquid. (584 mg, 69%). ¹HNMR (400 MHz, cdcl₃) δ 7.08 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H),4.48 (s, 2H), 2.56-2.50 (m, 2H), 1.62-1.50 (m, 2H), 1.48 (s, 9H),1.35-1.26 (m, 4H), 0.88 (t, J=6.9 Hz, 3H).

SO3-042 (3n)

Tert-butyl 2-(4-pentylphenoxy)acetate (SO3-042) (3n): This compound wassynthesized using the same protocol for SO2-180 3k except using4-hexylphenol (500 mg, 2.81 mmol), tert-butyl 2-bromoacetate (548 mg,2.81 mmol) and potassium carbonate (1.94 g, 14.10 mmol) The compoundSO3-042 3n was isolated as a colorless viscous liquid. (608 mg, 74%). ¹HNMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H),4.48 (s, 2H), 2.57-2.47 (m, 2H), 1.62-1.52 (m, 2H), 1.48 (s, 9H),1.28-1.17 (m, 6H), 0.87 (m, 3H).

SO3-058 (3o)

Tert-butyl 2-(4-cyclohexylphenoxy)acetate (SO3-058) (3o): This compoundwas synthesized using the same protocol for SO2-180 3k except using4-cyclohexylphenol (1.67 g, 9.47 mmol), tert-butyl 2-bromoacetate (1.85g, 9.47 mmol) and potassium carbonate (6.53 g, 47.4 mmol) The compoundSO3-042 30 was isolated as a colorless viscous liquid. (1.95 g, 71%). ¹HNMR (400 MHz, CDCl₃) δ 7.10 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H),4.47 (s, 2H), 2.48-2.37 (m, 1H), 1.86-1.76 (m, 6H), 1.41-1.29 (m, 4H).

SO3-072 (3p)

Tert-butyl 2-(4-isopropylphenoxy)acetate (SO3-072) (3p): This compoundwas synthesized using the same protocol for SO2-180 3k except using4-cyclohexylphenol (2.40 g, 17.62 mmol), tert-butyl 2-bromoacetate (3.44g, 17.62 mmol) and potassium carbonate (12.16 g, 88.10 mmol) Thecompound SO3-072 3o was isolated as a colorless viscous liquid. (3.00 g,68%). ¹H NMR (400 MHz, CDCl₃) δ 7.13 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8Hz, 2H), 4.48 (s, 2H), 2.94-2.80 (m, 1H), 1.49 (s, 9H), 1.22 (d, J=6.9Hz, 6H).

SO3-086 (3q)

Tert-butyl 2-(4-isobutylphenoxy)acetate (SO3-086) (3q): This compoundwas synthesized using the same protocol for SO2-180 3k except using4-isobutylphenol (660 mg, 4.39 mmol), tert-butyl 2-bromoacetate (857 mg,4.39 mmol) and potassium carbonate (3.03 g, 21.95 mmol) The compoundSO3-086 3q was isolated as a colorless viscous liquid. (836 mg, 72%). ¹HNMR (400 MHz, CDCl₃) δ 7.04 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H),4.49 (s, 2H), 2.40 (d, J=7.2 Hz, 2H), 1.89-1.74 (m, 1H), 1.48 (s, 9H),0.88 (d, J=6.6 Hz, 6H).

SO3-075 (3r)

Tert-butyl 2-(4-tert-butylphenoxy)acetate (SO3-072) (3r): This compoundwas synthesized using the same protocol for SO2-180 3k except using4-tert-butylphenol (1.63 g, 10.85 mmol), tert-butyl 2-bromoacetate (2.12g, 10.85 mmol) and potassium carbonate (7.49 g, 54.25 mmol) The compoundSO3-075 3r was isolated as a colorless viscous liquid. (2.07 g, 72%).

¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, J=8.9 Hz, 2H), 6.84 (d, J=8.9 Hz,2H), 4.50 (s, 2H), 1.50 (s, 9H), 1.30 (s, 9H).

SO1-136 (4a)

p-Tolyloxy-acetic acid (SO1-136) (4a): A solution of ethyl2-(p-tolyloxy)acetate (3a) (0.4 g, 2.4 mmol) an 10 ml NaOH (1M) and 10ml ethanol was refluxed overnight. Ethanol was evaporated and aqueoussolution was acidified with conc. HCl, the product was precipitated,filtered off and washed with water to give the pure compound SO1-136 4aas a white solid (0.34 g, 94%). ¹H NMR (400 MHz, DMSO) δ 12.94 (s, 1H),7.05 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 4.59 (s, 2H), 2.20 (s,3H).

SO1-161 (4b)

2-(4-Trifluoromethyl)phenoxy)acetic acid (SO1-161) (4b): This compoundwas synthesized using the same protocol for SO1-136 4a except usingethyl 2-(4-trifluoromethyl)phenoxy)acetate (3b) (2.70 g, 10.9 mmol),NaOH (1 M) (10 ml) and THF (10 ml). SO1-161 4b was isolated as a whitesolid. (2.35 g, 98%). ¹H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 7.64 (d,J=9.0 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 4.78 (s, 2H).

SO1-174 (4d)

2-(4-Chlorophenoxy)acetic acid (SO1-174) (4d): This compound wassynthesized using the same protocol for SO1-136 4a except using ethyl2-(4-chloromethyl)phenoxy)acetate (3d) (1.00 g, 4.66 mmol), NaOH (1 M)(10 ml) and THF (10 ml). SO1-161 4c was isolated as a white solid. (0.79g, 91%). ¹H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 7.31 (d, J=9.1 Hz, 2H),6.92 (d, J=9.1 Hz, 2H), 4.67 (s, 2H).

SO2-042 (4e)

2-(Biphenyl-4-yloxy)acetic acid (SO2-042) (4e): This compound wassynthesized using the same protocol for SO1-136 4a except using ethyl2-(biphenyl-4-yloxy)acetate (3e) (500 mg, 1.95 mmol), NaOH (1 M) (10 ml)and THF (10 ml). SO2-042 4e was isolated as a white solid. (410 mg,92%). ¹H NMR (400 MHz, DMSO) δ 7.58 (dd, J=8.0, 5.9 Hz, 4H), 7.41 (t,J=7.7 Hz, 2H), 7.29 (t, J=7.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 4.70 (s,2H).

SO2-041 (4g)

ethyl 2-(6-bromonaphthalen-2-yloxy)acetate

2-(6-Bromonapthalen-2-yloxy)acetic acid (SO2-041) (4g): This compoundwas synthesized using the same protocol for SO1-136 4a except usingethyl 2-(6-bromonapthalen-2-yloxy)acetate (3g) (500 mg, 1.62 mmol), NaOH(1 M) (10 ml) and THF (10 ml). SO2-041 4g was isolated as a white solid.(401 mg, 88%). ¹H NMR (400 MHz, DMSO) δ 8.09 (brs, 1H), 7.82 (d, J=9.0Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.54 (dd, J=8.7, 1.4 Hz, 1H), 7.28(brs, 1H), 7.23 (dd, J=8.9, 2.3 Hz, 1H), 4.78 (s, 2H).

SO2-056 (4h)

2-(m-Tolyloxy)acetic acid (SO2-056) (4h): This compound was synthesizedusing the same protocol for SO1-136 4a except using ethyl2-(m-tolyloxy)acetate (3h) (500 mg, 2.57 mmol), NaOH (1 M) (10 ml) andTHF (10 ml). SO2-056 4h was isolated as a white solid. (384 mg, 90%). ¹HNMR (400 MHz, DMSO) δ 7.13 (t, J=7.8 Hz, 1H), 6.76-6.65 (m, 3H), 4.61(s, 2H).

SO2-047 (4j)

2-(4-Ethylphenoxy)acetic acid (SO2-047) (4j): This compound wassynthesized using the same protocol for SO1-136 4a except using ethyl2-(4-ethylphenoxy)acetate (3j) (500 mg, 2.40 mmol), NaOH (1 M) (10 ml)and THF (10 ml). SO2-047 4j was isolated as a white solid. (394 mg,91%). ¹H NMR (400 MHz, DMSO) δ 7.09 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.7Hz, 2H), 2.62-2.38 (m, 2H), 1.12 (t, J=7.6 Hz, 3H).

SO2-182 (4k)

2-(4-Propylphenoxy)acetic acid (SO2-182) (4k): A solution of tert-Butyl2-(4-propylphenoxy)acetate (3k) (300 mg, 1.19 mmol) in dichloromethane(5 ml) and trifluoroacetic acid (5 ml) was stirred for 2 h at rt.Acetone (5 ml) was added to the reaction mixture. Excess trifluoroaceticacid and dichloromethane were evaporated to provide the pure acidSO2-182 4k as a pale yellow solid. (208 mg, 90%) ¹H NMR 400 MHz, DMSO) δ7.06 (d, J=8.5 Hz, 2H), 6.78 (d, J=8.6 Hz, 2H), 4.59 (s, 2H), 2.48-2.41(m, 2H), 1.56-1.47 (m, 2H), 0.84 (t, J=7.3 Hz, 3H).

SO3-024 (4l)

2-(4-Butylphenoxy)acetic acid (SO3-024) (4l): This compound wassynthesized using the same protocol for SO2-182 4k except usingtert-Butyl 2-(4-butylphenoxy)acetate (3l) (300 mg, 1.13 mmol) indichloromethane (5 ml) and trifluoroacetic acid (5 ml). SO3-024 4l wasisolated as a white solid. (212 mg, 90%). ¹H NMR (400 MHz, DMSO) δ 7.03(d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 4.47 (s, 1H), 2.53-2.39 (m,2H), 1.55-1.38 (m, 1H), 1.24 (dd, J=14.8, 7.4 Hz, 1H), 0.85 (t, J=7.3Hz, 1H).

SO3-046 (4m)

2-(4-Pentylphenoxy)acetic acid (SO3-046) (4m): This compound wassynthesized using the same protocol for SO2-182 4k except usingtert-Butyl 2-(4-pentylphenoxy)acetate (3m) (166 mg, 0.60 mmol) indichloromethane (5 ml) and trifluoroacetic acid (5 ml). SO3-046 4m wasisolated as a white solid. (123 mg, 93%).

SO3-044 (4n)

2-(4-Hexylphenoxy)acetic acid (SO3-044) (4n): This compound wassynthesized using the same protocol for SO2-182 4k except usingtert-Butyl 2-(4-hexylphenoxy)acetate (3n) (280 mg, 0.96 mmol) indichloromethane (5 ml) and trifluoroacetic acid (5 ml). SO3-044 4n wasisolated as a white solid. (222 mg, 98%).

¹H NMR (400 MHz, DMSO) δ 7.05 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H),4.56 (s, 2H), 2.53-2.35 (m, 2H), 1.57-1.39 (m, 2H), 1.28-1.17 (m, 6H),0.82 (t, J=6.7 Hz, 3H).

SO3-059 (4o)

2-(4-Cyclohexylphenoxy)acetic acid (SO3-059) (4o): This compound wassynthesized using the same protocol for SO2-182 4k except usingtert-Butyl 2-(4-cyclohexylphenoxy)acetate (3o) (1.00 g, 3.44 mmol) indichloromethane (10 ml) and trifluoroacetic acid (10 ml). SO3-059 4o wasisolated as a white solid. (0.75 g, 94%). ¹H NMR (400 MHz, CD₃OD) δ 7.11(d, J=8.5 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.60 (s, 2H), 2.49-2.37 (m,1H), 1.87-1.69 (m, 6H), 1.49-1.22 (m, 4H).

SO3-073 (4p)

2-(4-Isopropylphenoxy)acetic acid (SO3-073) (4p): This compound wassynthesized using the same protocol for SO2-182 4k except usingtert-Butyl 2-(4-isopropylphenoxy)acetate (3p) (700 mg, 2.80 mmol) indichloromethane (5 ml) and trifluoroacetic acid (5 ml). SO3-073 4p wasisolated as a pale yellow solid (506 mg, 93%). ¹H NMR (400 MHz, CDCl₃) δ7.17 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.67 (s, 2H), 2.92-2.81(m, 1H), 1.22 (d, J=6.9 Hz, 6H).

SO3-087 (4q)

2-(4-Isobutylphenoxy)acetic acid (SO3-087) (4q): This compound wassynthesized using the same protocol for SO2-182 4k except usingtert-Butyl 2-(4-isobutylphenoxy)acetate (3q) (250 mg, 0.95 mmol) indichloromethane (5 ml) and trifluoroacetic acid (5 ml). SO3-087 4q wasisolated as a white solid (188 mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.02(d, J=8.4 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H), 5.69 (s, 1H), 2.42 (d, J=7.2Hz, 2H), 1.98-1.69 (m, 1H), 0.91 (d, J=6.6 Hz, 6H).

SO3-077 (4r)

2-(4-Tert-butylphenoxy)acetic acid (SO3-077) (4r): This compound wassynthesized using the same protocol for SO2-182 4k except usingtert-Butyl 2-(4-tert-butylphenoxy)acetate (3r) (500 mg, 1.89 mmol) indichloromethane (5 ml) and trifluoroacetic acid (5 ml). SO3-077 4r wasisolated as a pale brown solid (358 mg, 91%). ¹H NMR (400 MHz, CDCl₃) δ9.68 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.68 (s,2H), 1.30 (s, 9H).

SO1-140 (5a)

p-Tolyloxy-acetyl chloride (SO1-140) (5a): To a solution ofp-tolyoxy-acetic acid (4a) (300 mg, 1.81 mmol) in 20 ml benzene thionylchloride (5 mL) was added and the mixture was refluxed for 3 h till aclear solution was formed. Excess thionyl chloride and benzene wereevaporated to give the pure compound SO1-140 5a as colorless liquid (313mg, 94%). ¹H NMR (400 MHz, CDCl₃) δ 7.11 (dd, J=8.7, 0.6 Hz, 1H), 6.80(d, J=8.7 Hz, 1H), 4.92 (d, J=3.4 Hz, 1H), 2.30 (s, 3H).

SO1-162 (5b)

2-(4-Trifluoromethyl)phenoxy)acetyl chloride (SO1-162) (5b): Thiscompound was synthesized using the same protocol for SO1-140 5a exceptusing 2-(4-trifluoromethyl)phenoxy)acetic acid (4b) (1.00 g, 4.54 mmol),SOCl₂ (5 ml) and benzene (5 ml). SO1-162 was isolated as colorlessliquid (996 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J=8.8 Hz, 2H),6.97 (d, J=8.7 Hz, 2H), 5.00 (s, 2H).

SO1-178 (5d)

2-(4-Chlorophenoxy)acetyl chloride (SO1-178) (5d): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-chlorophenoxy)acetic acid (4d) (1.00 g, 5.36 mmol), SOCl₂ (10 ml)and benzene (10 ml). SO1-178 5d was isolated as yellow solid (930 mg,91%). ¹H NMR (400 MHz, CDCl₃) δ 7.28 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.9Hz, 2H), 4.93 (s, 2H).

SO2-043 (5e)

2-(Biphenyl-4-yloxy)acetyl chloride (SO2-043) (5e): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(biphenyl-4-yloxy)acetic acid (4e) (410 mg, 1.80 mmol), SOCl₂ (10 ml)and benzene (10 ml). SO2-043 5e was isolated as yellow liquid (417 mg,94%). ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.52 (m, 4H), 7.43 (dd, J=8.2, 7.0Hz, 2H), 7.33 (t, J=7.4 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 4.99 (s, 2H).

SO2-029 (5f)

2-(4-Fluoro-phenoxy)acetyl chloride (SO2-029) (5f): This compound wassynthesized using the same protocol for SO1-140 5a except using(4-fluoro-phenoxy)-acetic acid (1.00 g, 5.88 mmol), SOCl₂ (10 ml) andbenzene (10 ml). SO2-029 5f was isolated as yellow solid (1.04 g, 94%).

SO2-044 (5g)

2-(6-Bromonapthalen-2-yloxy)acetyl chloride (SO2-044) (5g): Thiscompound was synthesized using the same protocol for SO1-140 5a exceptusing 2-(6-bromonapthalen-2-yloxy)acetic acid (4g) (500 mg, 1.78 mmol),SOCl₂ (10 ml) and benzene (10 ml). SO2-044 5g was isolated as yellowliquid (507 mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=1.7 Hz, 1H),7.69 (d, J=9.0 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.7, 1.9 Hz,1H), 7.21 (dd, J=9.0, 2.4 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 5.05 (s, 2H).

SO2-057 (5h)

2-(m-Tolyloxy)acetyl chloride (SO2-057) (5h): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(m-tolyloxy)acetic acid (4h) (750 mg, 4.51 mmol), SOCl₂ (10 ml) andbenzene (10 ml). SO2-057 5h was isolated as yellow liquid (758 mg, 91%).¹H NMR (400 MHz, CDCl₃) δ 7.20 (t, J=7.9 Hz, 1H), 6.88 (d, J=7.5 Hz,1H), 6.74-6.65 (m, 2H), 4.93 (s, 2H).

SO2-072 (5i)

2-(o-Tolyloxy)acetyl chloride (SO2-072) (5i): This compound wassynthesized using the same protocol for SO1-140 5a except using ethyl2-(o-tolyloxy)acetic acid (500 mg, 3.01 mmol), SOCl₂ (10 ml) and benzene(10 ml). SO2-072 5i was isolated as yellow liquid (511 mg, 92%). ¹H NMR(400 MHz, CDCl₃) δ 7.26 (t, J=2.8 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.83(d, J=8.5 Hz, 2H), 4.64 (s, 2H).

SO2-048 (5j)

2-(4-Ethylphenoxy)acetyl chloride (SO2-048) (5j): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-ethylphenoxy)acetic acid (4j) (300 mg, 1.66 mmol), SOCl₂ (5 ml) andbenzene (5 ml). SO2-048 5j was isolated as yellow liquid (313 mg, 95%).¹H NMR (400 MHz, CDCl₃) δ 7.15 (d, J=8.7 Hz, 1H), 6.84 (d, J=8.7 Hz,1H), 4.92 (s, 2H), 2.62 (q, J=7.6 Hz, 2H), 1.23 (dd, J=7.6 Hz, 3H).

SO2-183 (5k)

(4-Propylphenoxy)-acetyl chloride (SO2-183) (5k): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-propylphenoxy)acetic acid (4k) (200 mg, 1.03 mmol), SOCl₂ (5 ml)and benzene (5 ml). SO2-183 5k was isolated as a viscous yellow liquid.(208 mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.13 (d, J=8.3 Hz, 2H), 6.83(d, J=8.3 Hz, 2H), 4.93 (s, 2H), 2.55 (t, J=7.6 Hz, 2H), 1.70-1.55 (m,2H), 0.94 (t, J=7.3 Hz, 3H).

SO3-025 (5l)

2-(4-Butylphenoxy)acetyl chloride (SO3-025) (5l): This compound wassynthesized using the same protocol for SO1-140 5a except2-(4-butylphenoxy)acetic acid (4l) (200 mg, 0.96 mmol), SOCl₂ (5 ml) andbenzene (5 ml). SO3-125 51 was isolated as a viscous yellow liquid. (207mg, 95%). ¹H NMR (400 MHz, cdcl₃) δ 7.12 (d, J=8.0 Hz, 1H), 6.82 (d,J=8.1 Hz, 1H), 4.92 (s, 1H), 2.56 (t, J=7.6 Hz, 1H), 1.60-1.51 (m, 1H),1.34 (dd, J=14.7, 7.3 Hz, 1H), 0.93 (t, J=7.3 Hz, 2H).

SO3-049 (5m)

2-(4-Pentylphenoxy)acetyl chloride (SO3-049) (5m): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-pentylphenoxy)acetic acid (4m) (120 mg, 0.54 mmol), SOCl₂ (5 ml)and benzene (5 ml). SO3-049 5m was isolated as a viscous yellow liquid.(120 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ 7.12 (d, J=8.6 Hz, 2H), 6.81(d, J=8.6 Hz, 2H), 4.92 (s, 2H), 2.59-2.50 (m, 2H), 1.63-1.51 (m, 2H),1.39-1.23 (m, 4H), 0.89 (t, J=6.9 Hz, 3H).

SO3-048 (5n)

2-(4-Hexylphenoxy)acetyl chloride (SO3-049) (5n): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-hexylphenoxy)acetic acid (4n) (220 mg, 0.93 mmol) SOCl₂ (5 ml) andbenzene (5 ml). SO3-048 5n was isolated as a viscous yellow liquid. (227mg, 96%). ¹H NMR (400 MHz, cdcl₃) δ 7.10 (d, J=8.5 Hz, 2H), 6.80 (dd,J=8.6, 2.6 Hz, 2H), 4.91 (s, 2H), 2.53 (t, J=7.7 Hz, 2H), 1.61-1.49 (m,2H), 1.36-1.20 (m, 6H), 0.91-0.81 (m, 3H).

SO3-064 (5o)

2-(4-Cyclohexylphenoxy)acetyl chloride (SO3-049) (5o): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-cyclohexylphenoxy)acetic acid (4o) (200 mg, 0.85 mmol), SOCl₂ (5ml) and benzene (5 ml). SO3-064 5o was isolated as a viscous yellowliquid. (198 mg, 92%). ¹H NMR (400 MHz, CDC₃) δ 7.15 (d, J=8.7 Hz, 2H),0.82 (d, J=8.8 Hz, 2H), 4.92 (s, 2H), 2.51-2.40 (m, 1H), 1.88-1.68 (m,6H), 1.43-1.20 (m, 4H).

SO3-076 (5p)

2-(4-Isopropylphenoxy)acetyl chloride (SO3-076) (5p): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-isopropylphenoxy)acetic acid (4p) (260 mg, 1.34 mmol SOCl₂ (5 ml)and benzene (5 ml). SO3-076 5p was isolated as a viscous yellow liquid.(280 mg, 94%). ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J=8.5 Hz, 2H), 6.84(d, J=8.7 Hz, 2H), 4.93 (s, 2H), 2.94-2.86 (m, 1H), 1.24 (d, J=6.9 Hz,6H).

SO3-088 (5q)

2-(4-Isobutylphenoxy)acetyl chloride (SO3-088) (5q): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-isobutylphenoxy)acetic acid (4q) (127 mg, 0.61 mmol), SOCl₂ (5 ml)and benzene (5 ml). SO3-088 5q was isolated as a viscous yellow liquid.(131 mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.6 Hz, 2H), 6.81(d, J=8.6 Hz, 2H), 4.93 (s, 2H), 2.42 (d, J=7.2 Hz, 1H), 1.89-1.69 (m,1H), 0.89 (d, J=6.6 Hz, 6H).

SO3-078 (5r)

2-(4-Tert-butylphenoxy)acetyl chloride (SO3-078): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-tert-butylphenoxy)acetic acid (4r) (200 mg, 0.96 mmol), SOCl₂ (5ml) and benzene (5 ml). SO3-078 5r was isolated as a viscous yellowliquid. (207 mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J=9.0 Hz, 2H),6.84 (d, J=9.0 Hz, 2H), 4.94 (s, 2H), 1.31 (s, 9H).

SO2-169 (5s)

2-(4-Hydroxyphenoxy)acetyl chloride (SO2-169) (5s): This compound wassynthesized using the same protocol for SO1-140 5a except using(4-hydroxy-phenoxy)-acetic acid (4s) (300 mg, 1.78 mmol), SOCl₂ (5 ml)and benzene (5 ml). SO2-169 5s was isolated as a viscous yellow liquid.(302 mg, 91%). ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, J=8.6 Hz, 2H), 6.95(d, J=8.6 Hz, 2H), 4.95 (s, 2H).

SO3-090 (7c)

4-Chloro-N-hydroxy-benzamidine (SO3-090) (7c): 4-chlorobenzonitrile(1.00 g, 7.30 mmol) and hydroxylamine hydrochloride (1.02 g, 14.60 mmol)were dissolved in 7 ml of water. A solution of sodium carbonate (15.48g, 14.60 mmol) in water (5.0 ml) was cautiously added, and the resultingsolution was stirred and heated at 70° C. for 14 h. The solution wascooled to rt, saturated with sodium chloride and extracted with (4×15ml) EtAc. The solution was dried (MgSO₄) and the solvent was evaporatedto give the pure compound SO3-090 7c as a white solid (1.02 g, 82%). ¹HNMR (400 MHz, CD₃OD) δ 7.62 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H).LC-MS (ESI+) m/z 171.04 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₉H₉Cl₂N₂O₂ (M+H)⁺171.0320. found 171.0321.

SO3-099 (7e)

N-Hydroxy-pyridine-2-carboxamidine (SO3-099) (7e): This compound wassynthesized using the same protocol for SO3-090 7c except using2-cyanopyridine (1.24 g, 12 mmol), hydroxylamine hydrochloride (1.66 g,24 mmol) in 12 ml water and sodium carbonate (2.54 g, 24 mmol) in 9 mlwater. The compound SO3-099 7e was isolated as a white solid (1.5 g,93%). ¹H NMR (400 MHz, CD₃OD) δ 8.55 (ddd, J=4.9, 1.6, 1.0 Hz, 1H), 7.86(dd, J=5.1, 4.0 Hz, 1H), 7.77 (ddd, J=8.0, 7.5, 1.7 Hz, 1H), 7.37 (ddd,J=7.4, 4.9, 1.2 Hz, 1H).

SO3-005 (7f)

N-Hydroxy-nicotinamidine (SO3-005) (7f): This compound was synthesizedusing the same protocol for SO3-090 7c except using 3-cyanopyridine(0.62 g, 6.0 mmol), hydroxylamine hydrochloride (0.83 g, 12 mmol) in 6ml of water and A solution of sodium carbonate (1.27 g, 12 mmol) inwater (4.5 ml). SO3-005 7f was isolated as a white solid. (507 mg, 62%).¹H NMR (400 MHz, CD₃OD) δ 8.80 (dd, J=2.2, 0.7 Hz, 1H), 8.55 (dd, J=4.9,1.6 Hz, 1H), 8.09-8.04 (m, 1H), 7.45 (ddd, J=8.0, 4.9, 0.7 Hz, 1H).

¹H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 8.84 (dd, J=2.2, 0.8 Hz, 1H),8.54 (dd, J=4.8, 1.6 Hz, 1H), 8.01-7.97 (m, 1H), 7.39 (ddd, J=8.0, 4.8,0.8 Hz, 1H). LC-MS (ESI+) m/z 138.06 (M+H)⁺; HRMS (ESI+ve) m/zcalculated for C₆H₈N₃₀ (M+H)⁺138.0662. found 138.0659.

SO3-100 (7g)

N-Hydroxy-isonicotinamidine (SO3-100) (7g) This compound was synthesizedusing the same protocol for SO3-090 7c except using 4-cyanopyridine(1.24 g, 12 mmol), hydroxylamine hydrochloride (1.66 g, 24 mmol) in 12ml water and sodium carbonate (2.54 g, 24 mmol) in 9 ml water. Thecompound SO3-100 7g was isolated as a white solid (1.4 g, 87%). ¹H NMR(400 MHz, CD₃OD) δ 8.55 (d, J=6.3 Hz, 2H), 7.68 (d, J=6.3 Hz, 2H).

SO3-068 (7h)

N-Hydroxy-pyrimidine-5-carboxamidine (SO3-068) (7h): This compound wassynthesized using the same protocol for SO3-090 7c except usingpyrimidine-5-carbonitrile (0.167 g, 1.60 mmol), hydroxylaminehydrochloride (0.22 g, 3.20 mmol) in 1.6 ml water and sodium carbonate(0.34 g, 3.20 mmol) in 1.2 ml water. The compound SO3-068 7h wasisolated as a white solid (0.12 g, 55%). ¹H NMR (400 MHz, CD₃OD) δ 9.16(s, 1H), 9.03-9.01 (m, 2H).

SO3-092 (7i)

N-Hydroxy-pyrimidine-2-carboxamidine (SO3-092) (7i): This compound wassynthesized using the same protocol for SO3-090 7c except usingpyrimidin-2-carbonitrile (1.67 g, 16 mmol), hydroxylamine hydrochloride(2.20 g, 32 mmol) in 16 ml water and sodium carbonate (3.39 g, 32 mmol)in 12 ml water. The compound SO3-092 7i was isolated as a white solid(1.70 g, 77%). ¹H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 8.82 (d, J=4.9Hz, 2H), 7.48 (s, 1H), 5.82 (s, 2H).

SO3-045 (7j)

N-Hydroxy-pyrazine-2-carboxamidine (SO3-045) (7j): This compound wassynthesized using the same protocol for SO3-090 7c except usingpyrazine-2-carbonitrile (0.50 g, 4.80 mmol), hydroxylamine hydrochloride(0.66 g, 9.60 mmol) in 4.8 ml water and sodium carbonate (1.02 g, 9.60mmol) 3.6 ml water. The compound SO3-045 7j was isolated as a whitesolid (0.54 g, 82%). ¹H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.03 (d,J=1.4 Hz, 1H), 8.64-8.58 (m, 2H), 5.94 (s, 2H).

SO3-004 (8a)

(Z)—N′-(2-chloroacetoxy)-4-methylbenzimidamide (SO3-004) (8a): To asolution of N-hydroxy-4-methylbenzamidine (0.50 g, 3.30 mmol) in acetone(20 ml) chloroacetyl chloride (0.37 g, 3.30 mmol) was added slowly andthe mixture was stirred at rt for 30 min. Acetone was evaporated and theresidue was washed with sodium bicarbonate solution (5 ml) and water (10ml). The compound SO3-004 8a was dried and obtained as a white solid.(0.70 g, 88%). ¹H NMR (400 MHz, DMSO) δ 7.05 (d, J=8.6 Hz, 2H), 6.76 (d,J=8.6 Hz, 2H), 4.58 (s, 2H), 2.20 (s, 3H).

SO3-085 (8b)

(Z)—N′-(2-chloroacetoxy)-4-(trifluoromethyl)benzimidamide (SO3-085)(8b): This compound was synthesized using the same protocol for SO3-0048a except using 4-trifluoromethyl-N-hydroxy-benzamidine (100 mg, 4.89mmol) and chloroacetyl chloride (55 mg, 4.89 mmol). The compound SO3-0858b was isolated as a yellow solid (120 mg, 88%). ¹H NMR (400 MHz, CD₃OD)δ 7.92 (d, J=8.2 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 4.40 (s, 2H). LC-MS(ESI+) m/z 281.03 (M+H)⁺; HRMS (ESI+ve) m/z calculated for C₁₀H₉ClF₃N₂O₂(M+Na)⁺303.0119. found 303.0117.

SO2-053 (8c)

(Z)—N′-(2-chloroacetoxy)benzimidamide (SO2-053) (8c): This compound wassynthesized using the same protocol for SO3-004 8a except usingN-hydroxy-benzamidine (7c) (100 mg, 0.73 mmol) and chloroacetyl chloride(83 mg, 0.73 mmol). The compound SO2-053 8c was isolated as a whitesolid (136 mg, 87%). ¹H NMR (400 MHz, CD₃OD) δ 7.76-7.69 (m, 2H),7.56-7.40 (m, 3H), 4.39 (s, 2H).

SO3-091 (8d)

(Z)—N′-(2-chloroacetoxy)-4-chlorobenzimidamide (SO3-091) (8d): Thiscompound was synthesized using the same protocol for SO3-004 8a exceptusing 4-chloro-N-hydroxy-benzamidine (220 mg, 12.89 mmol) andchloroacetyl chloride (146 mg, 4.89 mmol). The compound SO3-091 8d wasisolated as a yellow solid (260 mg, 81%). ¹H NMR (400 MHz, CD₃OD) δ 7.71(d, J=7.6 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 4.38 (s, 1H). LC-MS (ESI+)m/z 246.99 (M+H)⁺; HRMS (ESI+ve) m/z calculated for C₉H₈Cl₂N₂O₂Na(M+Na)⁺268.9855. found 268.99855.

SO3-097 (8e)

(Z)—N′-(2-chloroacetoxy)picolinimidamide (SO3-097) (8e): This compoundwas synthesized using the same protocol for SO3-004 except using(Z)—N′-hydroxypicolinimidamide (7e) (130 mg, 0.95 mmol) and chloroacetylchloride (107 mg, 0.95 mmol). The compound SO3-097 8e was isolated as awhite solid (185 mg, 91%). ¹H NMR (400 MHz, CD₃OD) δ 8.63 (d, J=4.3 Hz,1H), 8.08 (d, J=8.0 Hz, 1H), 7.87 (td, J=7.8, 1.7 Hz, 1H), 7.49 (ddd,J=7.5, 4.8, 1.0 Hz, 1H), 4.43 (s, 2H).

SO2-098 (8f)

(Z)—N′-(2-chloroacetoxy)nicotinimidamide (SO2-098) (8f): This compoundwas synthesized using the same protocol for SO3-004 8a except usingN-hydroxy-nicotinamidine (7f) (125 mg, 0.91 mmol) and chloroacetylchloride (136 mg, 1.20 mmol). The compound SO2-098 8f was isolated as ayellow solid (161 mg, 83%). ¹H NMR (400 MHz, CD₃OD) δ 8.91 (dd, J=2.2,0.8 Hz, 1H), 8.67 (dd, J=5.0, 1.6 Hz, 1H), 8.20 (ddd, J=8.0, 2.2, 1.6Hz, 1H), 7.60-7.44 (m, 1H), 4.40 (s, 2H). LC-MS (ESI+) m/z 214.03(M+H)⁺; HRMS (ESI+ve) m/z calculated for C₈H₉ClN₃O₂ (M+H)⁺214.0378.found 214.0389.

SO3-098 (8g)

(Z)—N′-(2-chloroacetoxy)isonicotinimidamide (SO3-098) (8g): Thiscompound was synthesized using the same protocol for SO3-004 8a exceptusing (Z)—N′-(2-chloroacetoxy)picolinimidamide (7g) (200 mg, 1.46 mmol)and chloro acetyl chloride (165 mg, 1.46 mmol). The compound SO3-098 8gwas isolated as a yellow solid (274 mg, 88%). ¹H NMR (400 MHz, CD₃OD) δ8.55 (d, J=4.9 Hz, 2H), 7.68 (d, J=5.2 Hz, 2H), 4.19 (s, 2H). LC-MS(ESI+) m/z 214.04 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₈H₉ClN₃O₂(M+Na)⁺236.0197. found 236.0186.

SO3-069 (8h)

(Z)—N′-(2-chloroacetoxy)pyrimidine-5-carboximidamide (SO3-069) (8h):This compound was synthesized using the same protocol for SO3-004 8aexcept using N-hydroxy-pyrimidine-5-carboxamidine (7h) (110 mg, 0.80mmol) and chloroacetyl chloride (90 mg, 0.80 mmol). The compound SO3-0698h was isolated as a white solid (1.58 g, 92%). ¹H NMR (400 MHz, CD₃OD)δ 9.26 (s, 1H), 9.11 (s, 2H), 4.41 (s, 2H).

SO3-093 (8i)

(Z)—N′-(2-chloroacetoxy)pyrimidine-2-carboximidamide (SO3-093) (8i):This compound was synthesized using the same protocol for SO3-004 8aexcept using N-hydroxy-pyrimidine-2-carboxamidine (7i) (80 mg, 5.79mmol) and chloroacetyl chloride (65 mg, 5.79 mmol). The compound SO3-0938i was isolated as a white solid (115 mg, 90%). ¹H NMR (400 MHz, CD₃OD)δ 9.03 (d, J=4.9 Hz, 2H), 7.78 (d, J=4.9 Hz, 1H), 4.19 (s, 2H).

SO3-047 (8j)

(Z)—N′-(2-chloroacetoxy)pyrazine-2-carboximidamide (SO3-047) (8j): Thiscompound was synthesized using the same protocol for SO3-004 8a exceptusing (Z)—N′-hydroxypyrazine-2-carboximidamide (7j) (0.54 g, 3.90 mmol)and chloroacetyl chloride (0.44 g, 3.90 mmol). The compound SO3-047 8jwas isolated as a brown solid (0.76 g, 85%). ¹H NMR (400 MHz, CD₃OD) δ9.27 (d, J=1.2 Hz, 1H), 8.73-8.66 (m, 2H), 4.44 (s, 2H). LC-MS (ESI+)m/z 232.04 (M+NH4)⁺; HRMS (ESI+ve) m/z calculated forC₇H₇ClN₄O₂(M+Na)⁺237.0150. found 237.01401.

SO1-141 (9a)

5-Chloromethyl-3-p-tolyl-[1,2,4]oxadiazole (SO1-141) (9a):(Z)—N′-(2-chloropropanoyloxy)benzimidamide (8a) (400 mg, 1.76 mmol) wasrefluxed in toluene (20 ml) along with 4A⁰ molecular sieves for 2 hours.The reaction mixture was concentrated under vacuum to provide a cruderesidue. The crude residue was triturated with diethyl ether to afford5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (9a) as a pale yellow solid.(323 mg, 82%). ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.2 Hz, 2H), 7.27(dd, J=7.9, 0.5 Hz, 2H), 4.72 (s, 2H), 2.40 (s, 3H).

SO1-149-b2 (9b)

5-Chloromethyl-3-(4-trifluoromethylphenyl)[1,2,4]oxadiazole (SO1-149)(9b): This compound was synthesized using the same protocol for SO1-1419a except using(Z)—N′-(2-chloroacetoxy)-4-(trifluoromethyl)benzimidamide (8b) (150 mg,0.53 mmol) The compound SO1-149-b2 9b was isolated as a white solid (128mg, 91%). ¹H NMR (400 MHz, CD₃OD) δ 7.92 (d, J=8.1 Hz, 2H), 7.76 (d,J=8.3 Hz, 2H), 4.71 (s, 2H).

SO1-167 (9c)

5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole (SO1-167) (9c): This compoundwas synthesized using the same protocol for SO1-141 9a except using(Z)—N′-(2-chloroacetoxy)benzimidamide (8c) (300 mg, 1.33 mmol) wasrefluxed in toluene (20 ml) The compound5-chloromethyl-3-phenyl-[1,2,4]oxadiazole (9c) was isolated as a yellowsolid. (238 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=8.0 Hz, 2H),7.52-7.40 (m, 2H), 4.74 (s, 2H).

SO1-153-b2 (9d)

5-Chloromethyl-3-(4-chloro-phenyl)-[1,2,4]oxadiazole (SO1-153-b2) (9d):This compound was synthesized using the same protocol for SO1-141 9aexcept using (Z)—N′-(2-chloroacetoxy)-4-chlorobenzimidamide (8d) (200mg, 0.81 mmol) The compound SO1-153-b2 (9d) was isolated as a whitesolid (154 mg, 83%). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=8.7 Hz, 2H),7.47 (d, J=8.7 Hz, 2H), 4.75 (s, 2H).

SO2-065 (9e)

5-(Chloromethyl)-3-(pyridin-2-yl)-1,2,4-oxadiazole (SO2-065) (9e): Thiscompound was synthesized using the same protocol for SO1-141 9a exceptusing (Z)—N′-(2-chloroacetoxy)picolinimidamide (8e) (100 mg, 0.47 mmol)The compound SO2-065 9e was isolated as a white solid (86 mg, 94%). ¹HNMR (400 MHz, CDCl₃) δ 8.81 (ddd, J=4.8, 1.6, 1.0 Hz, 1H), 8.14 (dt,J=7.9, 1.1 Hz, 1H), 7.87 (td, J=7.8, 1.8 Hz, 1H), 7.46 (ddd, J=7.7, 4.8,1.2 Hz, 1H), 4.79 (s, 2H). LC-MS (ESI+) m/z 196.03 (M+H)⁺; HRMS (ESI+ve)m/z calculated for C₈H₇ClN₃O (M+H)⁺196.0272. found 196.0264.

SO2-055 (9f)

5-(Chloromethyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole (SO2-055) (9f): Thiscompound was synthesized using the same protocol for SO1-141 9a exceptusing (Z)—N′-(2-chloroacetoxy)nicotinimidamide (80 (100 mg, 0.47 mmol)The compound SO2-055 9f was isolated as a yellow solid (83 mg, 90%). ¹HNMR (400 MHz, CDCl₃) δ 9.25 (dd, J=2.2, 0.9 Hz, 1H), 8.70 (dd, J=4.9,1.7 Hz, 1H), 8.38-8.24 (m, 1H), 7.38 (ddd, J=8.0, 4.9, 0.9 Hz, 1H).LC-MS (ESI+) m/z 196.03 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₈H₇ClN₃O (M+H)⁺196.0272. found 196.0269.

SO2-063 (9g)

5-(Chloromethyl)-3-(pyridin-4-yl)-1,2,4-oxadiazole (SO2-063) (9g): Thiscompound was synthesized using the same protocol for SO1-141 9a exceptusing (Z)—N′-(2-chloroacetoxy)isonicotinimidamide (8g) (100 mg, 0.47mmol) The compound SO2-063 9g was isolated as a yellow solid (77 mg,84%). ¹H NMR (400 MHz, CDCl₃) δ 8.79 (dd, J=5.3, 0.7 Hz, 2H), 7.94 (d,J=6.1 Hz, 2H), 4.77 (s, 2H).

SO3-055 (28)

Pyrimidine-5-carboxamide (SO3-055): A mixture of pyrimidine-5-carboxylicacid ethyl ester (1.57 g, 10.32 mmol) and NH₄OH (1.2 ml) were heated ina sealed tube at 50° C. for 14 h. The solid precipitated was filteredoff (300 mg) and filtrate then concentrated and the residue was stirredin ethanol/ethyl acetate (v/v 1/4, 13 ml) at rt for 2 h. The whiteprecipitate was collected by filtration and dried to give the finalcompound SO3-055 as a white solid. (525 mg, 65%). ¹H NMR (400 MHz, DMSO)δ 9.29 (s, 1H), 9.15 (s, 2H), 8.31 (brs, 1H), 7.82 (brs, 1H).

SO3-067 (29)

Pyrimidine-5-carbonitrile (SO3-067): To a suspension ofpyrimidine-5-carboxamide (SO3-055) (262 mg, 2.12 mmol) and triethylamine (481 mg, 4.24 mmol) in anhydrous dichoromethane (15 ml) was slowlyadded a solution of trifluoroacetic anhydride (0.36 ml in 4 mldichloromethane) at 0° C. The reaction mixture was stirred at 0° C. toRT for 2 h. and quenched with water (2 ml) and washed with NaOH (1 N, 5ml) and brine (2×5 ml). Organic solvent was dried (MgSO₄) and evaporatedat less than 30° C. to provide SO3-067 as a pale yellow solid. (174 mg,78%). ¹H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 9.31 (s, 2H).

SO3-070 (9h)

5-(Chloromethyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole (SO3-070) (9h):This compound was synthesized using the same protocol for SO1-141 9aexcept using (Z)—N′-(2-chloroacetoxy)pyrimidine-5-carboximidamide (8h)(140 mg, 0.65 mmol) The compound SO3-070 9h was isolated as a yellowsolid (112 mg, 87%). ¹H NMR (400 MHz, CDCl₃) δ 9.61-9.17 (m, 3H), 4.78(s, 2H).

SO3-094 (9i)

5-(Chloromethyl)-3-(pyrimidin-2-yl)-1,2,4-oxadiazole (SO3-094) (9i):This compound was synthesized using the same protocol for SO1-141 9aexcept using (Z)—N′-(2-chloroacetoxy)pyrimidine-2-carboximidamide (8i)(500 mg, 2.33 mmol) The compound SO3-094 9i was isolated as a whitesolid (389 mg, 85%). ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J=4.9 Hz, 2H),7.47 (t, J=4.9 Hz, 1H), 4.80 (s, 2H). LC-MS (ESI+) m/z 197.03 (M+H)⁺;HRMS (ESI+ve) m/z calculated for C₇H₆ClN₄O (M+H)⁺197.0225. found197.0224.

SO3-052 (9j)

5-(Chloromethyl)-3-(pyrazin-2-yl)-1,2,4-oxadiazole (SO3-052) (9j): Thiscompound was synthesized using the same protocol for SO1-141 9a exceptusing (Z)—N′-(2-chloroacetoxy)pyrazine-2-carboximidamide (8j) (200 mg,0.93 mmol) The compound SO3-052 9j was isolated as a white solid (150mg, 82%). ¹H NMR (400 MHz, CDCl₃) δ 9.32 (d, J=1.5 Hz, 1H), 8.72 (dd,J=2.4, 1.6 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H), 7.20 (s, 1H), 4.75 (s, 2H).

LC-MS (ESI+) m/z 197.02 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₇H₆ClN₄O (M+H)⁺196.0225. found 196.0223.

SO1-142 (10a)

Isopropyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (SO1-142) (10a):To a solution of 5-chloromethyl-3-p-tolyl-[1,2,4]oxadiazole (9a) (300mg, 1.44 mmol) in 20 mL acetonitrile was added diisopropyl amine (0.17g, 2.88 mmol) and potassium carbonate (994 mg, 7.2 mmol) and the mixturewas refluxed for 30 min. Acetonitrile was evaporated and the residue wasdissolved in ethyl acetate and washed with water. Organic solvent wasdried (MgSO₄) and evaporated to give the pure compound SO1-142 10a as awhite solid (303 mg, 91%). ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.2 Hz,2H), 7.25 (dd, J=7.8, 0.7 Hz, 2H), 4.08 (s, 2H), 2.92 (hept, J=6.2 Hz,1H), 2.38 (s, 3H), 1.10 (d, J=6.2 Hz, 6H).

SO1-155 (10b)

Isopropyl-(3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine(SO1-155) (10b): This compound was synthesized using the same protocolfor SO1-142 10a except using5-chloromethyl-3-(4-trifluoromethylphenyl)-[1,2,4]oxadiazole (9b) (100mg, 0.38 mmol), isopropyl amine (45 mg, 0.76 mmol) and potassiumcarbonate (262 mg, 1.90 mmol). The compound SO1-155 10b was isolated asa viscous yellow liquid (997 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ 8.21(dd, J=8.8, 0.7 Hz, 2H), 7.74 (dd, J=8.7, 0.6 Hz, 2H), 4.14 (s, 2H),2.93 (hept, J=6.2 Hz, 1H), 1.13 (d, J=6.2 Hz, 6H).

SO1-168 (10c)

Isopropyl-(3-phenyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (SO1-168) (10c):This compound was synthesized using the same protocol for SO1-142 10aexcept using5-chloromethyl-3-(4-trifluoromethylphenyl)-[1,2,4]oxadiazole (9c) (100mg, 0.38 mmol), isopropyl amine (45 mg, 0.76 mmol) and potassiumcarbonate (262 mg, 1.90 mmol). The compound SO1-168 10c was isolated asa white solid (349 mg, 98%). ¹H NMR (400 MHz, CDCl₃) δ 8.15-8.00 (m,2H), 7.59-7.32 (m, 3H), 4.10 (s, 2H), 2.90 (hept, J=6.2 Hz, 1H), 1.10(d, J=6.2 Hz, 6H). LC-MS (ESI+) m/z 218.13 (M+H)⁺; HRMS (ESI+ve) m/zcalculated for C₁₂H₁₆N₃O (M+H)⁺218.1288. found 218.1286.

SO1-156 (10d)

[3-(4-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl)methyl]isopropyl-amineSO1-156 (10d): This compound was synthesized using the same protocol forSO1-142 10a except using5-chloromethyl-3-(4-chloro-phenyl)-[1,2,4]oxadiazole (9d) (290 mg, 1.27mmol), isopropyl amine (150 mg, 2.53 mmol) and potassium carbonate (283mg, 6.35 mmol). The pure compound 10d was isolated as a pale yellowsolid. (75 mg, 84%). ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=8.6 Hz, 2H),7.42 (d, J=8.5 Hz, 2H), 4.09 (s, 2H), 2.89 (hept, J=6.2 Hz, 1H), 1.10(d, J=6.2 Hz, 6H).

LC-MS (ESI+) m/z 252.08 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₂H₁₅ClN₃O (M+H)⁺ 252.0898. found 252.0887.

LC-MS (ESI+) m/z 286.13 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₃H₁₅ClF₃N₃O (M+H)⁺ 286.1162. found 286.1156.

SO2-071 (10e)

N-((3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine(SO2-071) (10e): This compound was synthesized using the same protocolfor SO1-142 10a except using5-(chloromethyl)-3-(pyridin-2-yl)-1,2,4-oxadiazole (9e) (75 mg, 0.38mmol), isopropyl amine (34 mg, 0.58 mmol) and potassium carbonate (262mg, 1.90 mmol). The compound SO2-071 10e was isolated as a yellow solid(75 mg, 89%). ¹H NMR (400 MHz, CDCl₃) δ 8.80 (ddd, J=4.8, 1.7, 0.9 Hz,1H), 8.13 (d, J=7.9 Hz, 1H), 7.85 (td, J=7.8, 1.8 Hz, 1H), 7.43 (ddd,J=7.6, 4.8, 1.2 Hz, 1H), 4.15 (s, 2H), 2.91 (hept, J=6.2 Hz, 1H), 1.11(d, J=6.2 Hz, 6H).

LC-MS (ESI+) m/z 219.13 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₁H₁₅N₄O (M+H)⁺219.1240. found 219.1244.

SO2-060 (10f)

N-((3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine(SO2-060) (100: This compound was synthesized using the same protocolfor SO1-142 10a except using5-(chloromethyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole (90 (80 mg, 0.41mmol), isopropyl amine (48 mg, 0.82 mmol) and potassium carbonate (283mg, 2.05 mmol). The pure compound SO2-060 10f was isolated as a paleyellow solid. (75 mg, 84%). ¹H NMR (400 MHz, CDCl₃) δ 9.33-9.25 (m, 1H),8.73 (dd, J=4.9, 1.7 Hz, 1H), 8.34 (dt, J=8.0, 1.9 Hz, 1H), 7.41 (ddd,J=8.0, 4.9, 0.8 Hz, 1H), 4.13 (s, 2H), 2.91 (hept, J=6.2 Hz, 1H), 1.12(d, J=6.2 Hz, 6H). LC-MS (ESI+) m/z 219.13 (M+H)⁺; HRMS (ESI+ve) m/zcalculated for C₁₁H₁₅N₄O (M+H)⁺219.1240. found 219.1241.

SO2-064 (10g)

N-((3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine(SO2-064) (10g): This compound was synthesized using the same protocolfor SO1-142 10a except using5-(chloromethyl)-3-(pyridin-4-yl)-1,2,4-oxadiazole (9g) (26 mg, 0.13mmol), isopropyl amine (15 mg, 0.26 mmol) and potassium carbonate (90mg, 0.65 mmol). The compound SO2-064 10g was isolated as a pale yellowsolid (23 mg, 81%). ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J=6.0 Hz, 2H),7.92 (d, J=6.1 Hz, 2H), 4.12 (s, 2H), 2.91 (hept, J=6.2 Hz, 1H), 1.10(d, J=6.2 Hz, 6H).

LC-MS (ESI+) m/z 219.12 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₁H₁₅N₄O (M+H)⁺219.1240. found 219.1251.

SO3-071 (10h)

N-((3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine(SO2-071) (10h): This compound was synthesized using the same protocolfor SO1-142 10a except using5-(chloromethyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole (9h) (80 mg, 0.41mmol), isopropyl amine (49 mg, 0.82 mmol) and potassium carbonate (283mg, 2.05 mmol). The compound SO3-071 10h was isolated as a yellow solid(289 mg, 88%). ¹H NMR (400 MHz, CDCl₃) δ 9.33 (d, J=0.7 Hz, 2H), 9.29(s, 1H), 4.10 (d, J=0.6 Hz, 2H), 2.86 (hept, J=6.2 Hz, 1H), 1.07 (dd,J=6.2, 0.7 Hz, 6H). LC-MS (ESI+) m/z 220.13 (M+H)⁺; HRMS (ESI+ve) m/zcalculated for C₁₀H₁₄N₅O (M+H)⁺220.1193. found 220.1213.

SO3-095 (10i)

N-((3-(pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine(SO3-095) (10i): This compound was synthesized using the same protocolfor SO1-142 10a except using5-(chloromethyl)-3-(pyrimidin-2-yl)-1,2,4-oxadiazole (9i) (300 mg, 1.53mmol), isopropyl amine (180 mg, 3.05 mmol) and potassium carbonate (1058mg, 7.65 mmol). The compound SO3-095 10i was isolated as a yellow solid(289 mg, 86%). ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, J=4.9 Hz, 2H), 7.40(t, J=4.9 Hz, 1H), 4.12 (s, 2H), 2.81 (hept, J=6.2 Hz, 1H), 1.03 (d,J=6.2 Hz, 6H). LC-MS (ESI+) m/z 220.11 (M+H)⁺; HRMS (ESI+ve) m/zcalculated for C₁₀H₁₄N₅O (M+H)⁺220.1193. found 220.1193.

SO3-053 (10j)

N-((3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine(SO2-071) (10j): This compound was synthesized using the same protocolfor SO1-142 10a except using5-(chloromethyl)-3-(pyrazin-2-yl)-1,2,4-oxadiazole (9j) (150 mg, 0.76mmol), isopropyl amine (90 mg, 1.52 mmol) and potassium carbonate (524mg, 3.80 mmol). The compound SO2-071 10j was isolated as a yellowviscous liquid (150 mg, 90%). ¹H NMR (400 MHz, CDCl₃) δ 9.37 (d, J=1.4Hz, 1H), 8.87-8.54 (m, 2H), 4.18 (s, 2H), 2.91 (hept, J=6.2 Hz, 1H),1.12 (d, J=6.2 Hz, 6H). LC-MS (ESI+) m/z 220.13 (M+H)⁺; HRMS (ESI+ve)m/z calculated for C₁₀H₁₄N₅O (M+H)⁺220.1193. found 220.1198.

SO1-183 (10k)

Methyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (SO1-183) (10k):This compound was synthesized using the same protocol for SO1-142 10aexcept using 5-chloromethyl-3-p-tolyl-[1,2,4]oxadiazole (8a) (85 mg,0.41 mmol) and methyl amine (1 ml from 40% solution in water) andpotassium carbonate (282 mg, 2.04 mmol). The compound SO1-183 10k wasobtained as a yellow viscous liquid (90 mg, 95%).

¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.2 Hz, 2H), 7.29 (d, J=7.9 Hz,2H), 4.07 (s, 2H), 2.55 (s, 3H), 2.41 (s, 3H).

LC-MS (ESI+) m/z 204.12 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₁H₁₄N₃O (M+H)⁺204.1131. found 204.1141.

SO2-008 (10l)

Ethyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (SO2-008) (10l):This compound was synthesized using the same protocol for SO1-142 10aexcept using 5-chloromethyl-3-p-tolyl-[1,2,4]oxadiazole (8a) (80 mg,0.38 mmol) and ethyl amine (1 ml from 40% solution in water) andpotassium carbonate (265 mg, 1.92 mmol). The compound SO2-008 101 wasobtained as a yellow viscous liquid (73 mg, 88%). ¹H NMR (400 MHz,CDCl₃) δ 7.96 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 4.11 (s, 2H),2.77 (q, J=7.1 Hz, 2H), 2.41 (s, 3H), 1.16 (t, J=7.1 Hz, 3H). LC-MS(ESI+) m/z 218.13 (M+H)⁺; HRMS (ESI+ve) m/z calculated for C₁₂H₁₆N₃O(M+H)⁺218.1288. found 218.1290.

SO1-154 (10 m)

Isobutyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (SO1-154) (10m):This compound was synthesized using the same protocol for SO1-142 10aexcept using 5-chloromethyl-3-p-tolyl-[1,2,4]oxadiazole (8a) (100 mg,0.48 mmol) and isobutyl amine (70 mg, 0.96 mmol) and potassium carbonate(331 mg, 2.40 mmol). The compound SO1-154 10m was obtained as a whitesolid (110 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=8.1 Hz, 2H),7.27 (d, J=7.8 Hz, 2H), 4.08 (s, 2H), 2.50 (d, J=6.8 Hz, 2H), 2.39 (s,3H), 1.83-1.69 (m, 1H), 0.92 (d, J=6.7 Hz, 6H).

SO2-005 (10n)

C-(3-p-Tolyl-[1,2,4]oxadiazol-5-yl)-methylamine (SO2-005) (10n): Asolution of2-(3-p-tolyl-)-[1,2,4]oxadiazol-5-ylmethyl)-isoindole-1,3-dione (120 mg,0.38 mmol) and hydrazine (20 mg, 0.45 mmol) were refluxed in 20 mlethanol. The reaction was monitored by TLC and completed in 30 min.Ethanol was evaporated and the residue was dissolved in EtAc and washedwith 1M NaOH solution (5×10 ml) and water (2×10 ml). Organic solvent wasdried (MgSO₄) and evaporated to give the pure compound SO2-005 10n as ayellow solid (55 mg, 77%).

¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J=8.2 Hz, 2H), 7.21 (dd, J=8.0, 0.4Hz, 2H), 4.07 (s, 2H), 2.34 (s, 3H).

SO2-067 (10o)

Tert-butyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (SO2-067)(10o): This compound was synthesized using the same protocol for SO1-14210a except using 5-chloromethyl-3-p-tolyl-[1,2,4]oxadiazole (8a) (88 mg,0.43 mmol) and tert-buyl amine (37 mg, 0.51 mmol) and potassiumcarbonate (298 mg, 2.15 mmol). The compound SO2-067 10o was obtained asa yellow viscous liquid (833 mg, 79%).

¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.2 Hz, 2H), 7.28 (dd, J=8.5, 0.5Hz, 2H), 4.07 (s, 2H), 2.41 (s, 3H), 1.19 (s, 9H). LC-MS (ESI+) m/z246.15 (M+H)⁺; HRMS (ESI+ve) m/z calculated for C₁₄H₁₉N₃O(M+H)⁺246.1601. found 246.1593.

SO3-082 (10p)

Cyclopropyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (SO3-082)(10p): This compound was synthesized using the same protocol for SO1-14210a except using 5-chloromethyl-3-p-tolyl-[1,2,4]oxadiazole (8a) (100mg, 0.48 mmol) and cyclopropyl amine (55 mg, 0.96 mmol) and potassiumcarbonate (350 mg, 2.40 mmol). The compound SO3-082 10p was obtained asa yellow viscous liquid (1024 mg, 93%).

¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.2 Hz, 2H), 7.28 (dd, J=7.9, 0.6Hz, 2H), 4.14 (s, 2H), 2.41 (s, 3H), 2.33-2.17 (m, 1H), 0.61-0.33 (m,4H). LC-MS (ESI+) m/z 230.13 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₃H₁₆ClN₃O (M+H)⁺230.1288. found 230.1285.

SO2-004 (30)

2-(3-p-Tolyl-)-[1,2,4]oxadiazol-5-ylmethyl)-isoindole-1,3-dione(SO2-004): A solution of 5-Chloromethyl-3-p-tolyl-[1,2,4]oxadiazole (100mg, 0.48 mmol), phthalimide (70 mg, 0.48 mmol) and potassium carbonate(330 mg, 2.3 mmol) were refluxed in acetonitrile (15 ml) for 1 h.Acetonitrile was evaporated and the residue was dissolved in ethylacetate and washed with water, the solvent was dried (MgSO₄) andevaporated to give the pure compound as a white solid (140 mg, 91%). ¹HNMR (400 MHz, CDCl₃) δ 7.96-7.90 (m, 2H), 7.89 (d, J=8.2 Hz, 2H),7.81-7.77 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 5.16 (s, 2H), 2.38 (s, 3H).LC-MS (ESI+) m/z 320.10 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₈H₁₄N₃O₃ (M+H)⁺320.1030. found 320.1041.

SO2-085 (24)

(Z)—N′-(2-chloropropanoyloxy)benzimidamide (SO2-085) (24): To a solutionof oxime (300 mg, 2.20 mmol) in dichloromethane (15 ml) at 0° C. wasadded chloroacetyl chloride (249 mg, 2.20 mmol) dropwise and the mixturewas warmed up to rt and stirred for 14 h. The mixture was extracted withsaturated sodium bicarbonate (2×15 ml) and water (15 ml) and dried(MgSO₄) and evaporated to give the colorless viscous compound SO2-085(24). (446 mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J=8.3, 1.3 Hz,2H), 7.49-7.46 (m, 1H), 7.45-7.37 (m, 2H), 3.85 (t, J=6.7 Hz, 2H), 3.01(t, J=6.7 Hz, 2H).

SO2-086 (25)

5-(2-Chloro-ethyl)-3-phenyl)-[1,2,4]oxadiazole (SO2-086) (25): Thiscompound was synthesized using the same protocol for SO1-141 9a exceptusing (Z)—N′-(2-chloroacetoxy)-4-(trifluoromethyl)benzimidamide (24)(400 mg, 1.50 mmol) The compound SO2-086 25 was isolated as a viscouscolorless liquid (254 mg, 81%). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (dd,J=7.9, 1.8 Hz, 2H), 7.54-7.45 (m, 3H), 3.99 (t, J=6.9 Hz, 2H), 3.43 (t,J=6.9 Hz, 2H).

SO2-088 (26)

Isopropyl-[2-(3-phenyl)-[1,2,4]oxadiazol5-yl)-ethyl]-amine (SO2-088)(26): This compound was synthesized using the same protocol for SO1-14210a except using 5-(2-chloro-ethyl)-3-phenyl)-[1,2,4]oxadiazole (25)(100 mg, 0.48 mmol), isopropyl amine (42 mg, 0.72 mmol) and potassiumcarbonate (331 mg, 2.40 mmol). The compound SO2-088 (26) was isolated asa brown viscous liquid (955 mg, 86%). ¹H NMR (400 MHz, CDCl₃) δ 8.00(dd, J=8.0, 1.8 Hz, 2H), 7.55-7.34 (m, 3H), 3.09-3.07 (m, 4H), 2.84(hept, J=6.2 Hz, 1H), 1.03 (d, J=6.3 Hz, 6H).

SO2-135 (13a)

2-p-Tolyloxy-propionic acid ethyl ester (SO2-135) (13a): This compoundwas synthesized using the same protocol for SO1-133 5a except usingp-cresol (1.00 g, 9.24 mmol), 2-bromo-propionic acid ethyl ester (1.81g, 10.00 mmol) and potassium carbonate (6.35 g, 46.00 mmol). SO2-135 13awas isolated as a yellow viscous liquid (150 mg, 78%). ¹H NMR (400 MHz,CDCl₃) δ 7.06 (dd, J=8.7, 0.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 4.70 (q,J=6.8 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.27 (s, 3H), 1.60 (d, J=6.8 Hz,3H), 1.25 (t, J=7.1 Hz, 3H).

SO3-101 (13b)

2-(4-Propyl-phenoxy)-propionic acid ethyl ester (SO3-101) (13b): Thiscompound was synthesized using the same protocol for SO1-133 5a exceptusing p-cresol (1.00 g, 7.34 mmol), 2-bromo-propionic acid ethyl ester(1.46 g, 8.08 mmol) and potassium carbonate (5.06 g, 36.70 mmol).SO3-10113b was isolated as a colorless viscous liquid (141 mg, 81%). ¹HNMR (400 MHz, CDCl₃) δ 7.06 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H),4.70 (q, J=6.8 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.50 (t, J=7.4 Hz, 2H),2.46-2.36 (m, 2H), 1.65-1.53 (m, 2H), 1.60 (d, J=6.8 Hz, 3H), 1.24 (t,J=7.1 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

SO2-138 (14a)

2-p-Tolyloxy-propionic acid (SO2-138) (14a): This compound wassynthesized using the same protocol for SO1-136 except using2-p-tolyloxy-propionic acid ethyl ester (13a) (500 mg, 2.40 mmol), NaOH(1 M) (10 ml) and THF (10 ml). SO2-138 14a was isolated as a yellowsolid. (368 mg, 85%). ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=8.5 Hz, 2H),6.80 (d, J=8.6 Hz, 2H), 4.76 (q, J=6.9 Hz, 1H), 2.29 (s, 3H), 1.65 (d,J=6.9 Hz, 3H).

SO3-006 (14b)

(S)-2-(p-tolyloxy)propanoic acid (SO3-006) (14b): NaH (60% suspension,60 mg, 1.50 mmol) was added to a solution of (S)-bromopropionic acid(231 mg, 1.50 mmol) in THF (10 ml). In a separate vessel NaH (60%suspension, 120 mg, 3.00 mmol) was added to a solution of p-cresol (324mg, 3.00 mmol). The phenolate solution was calculated into the2-bromopropionate solution, and stirred at room temperature for 0.5 h.The reaction was quenched with NaOH solution (20 ml, 2 N NaOH), and keptstirring at room temperature for another hour. The reaction wasacidified with HCl (2M) up to pH=1, and extracted with Et₂O (3×25 ml).The Et₂O extract was dried over anhydrous (MgSO₄) and concentrated. Theresidue was purified by column chromatography to yield the acid SO3-00614b as a white solid. (144 mg, 62%).

¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz,2H), 4.76 (q, J=6.9 Hz, 1H), 2.29 (s, 3H), 1.64 (d, J=6.9 Hz, 3H).

SO3-062 (14c)

(R)-2-(p-tolyloxy)propanoic acid (SO3-062) (14c): NaH (60% suspension,60 mg, 1.50 mmol) was added to a solution of (R)-bromopropionic acid(231 mg, 1.50 mmol) in THF (10 ml). In a separate vessel NaH (60%suspension, 120 mg, 3.00 mmol) was added to a solution of p-cresol (324mg, 3.00 mmol). The phenolate solution was calculated into the2-bromopropionate solution, and stirred at room temperature for 5 h. Thereaction was quenched with NaOH solution (20 ml, 2 M NaOH), and keptstirring at room temperature for another hour. The reaction wasacidified with HCl (2M) up to pH=1, and extracted with Et₂O (3×25 ml).The Et₂O extract was dried over anhydrous (MgSO₄) and concentrated. Theresidue was purified by column chromatography to yield the acid SO3-06214c as a white solid. (230 mg, 85%). ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d,J=8.6 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 4.76 (q, J=6.8 Hz, 1H), 2.29 (s,3H), 1.64 (d, J=6.9 Hz, 3H).

SO3-103 (14d)

2-(4-Propyl-phenoxy)-propionic acid (SO3-103) (14d): This compound wassynthesized using the same protocol for SO1-136 except using2-(4-propyl-phenoxy)-propionic acid ethyl ester (13b) (200 mg, 0.85mmol), NaOH (1 M) (10 ml) and THF (10 ml). SO3-103 14d was isolated as ayellow solid. (155 mg, 88%). ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=8.6Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 4.76 (q, J=6.9 Hz, 1H), 2.52 (t, J=7.3Hz, 2H), 1.65 (d, J=6.9 Hz, 3H), 1.63-1.54 (m, 2H), 0.93 (dd, J=8.2, 6.4Hz, 3H).

SO3-102 (14e)

(S)-2-(4-Propyl-phenoxy)-propanoic acid (SO3-102) (14e): NaH (60%suspension, 26 mg, 0.65 mmol) was added to a solution of(S)-bromopropionic acid (100 mg, 0.65 mmol) in THF (10 ml). In aseparate vessel NaH (60% suspension, 52 mg, 1.30 mmol) was added to asolution of p-propylphenol (1.77 g, 1.30 mmol). The phenolate solutionwas calculated into the 2-bromopropionate solution, and stirred at roomtemperature for 0.5 h. The reaction was quenched with NaOH solution (20ml, 2 M NaOH), and kept stirring at room temperature for another hour.The reaction was acidified with HCl (2M) up to pH=1, and extracted withEt₂O (3×25 ml). The Et₂O extract was dried over anhydrous (MgSO₄) andconcentrated. The residue was purified by column chromatography to yieldthe acid SO3-102 14e as a viscous yellow liquid. (112 mg, 83%). ¹H NMR(400 MHz, CDCl₃) δ 7.09 (d, J=8.7 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 4.76(q, J=6.9 Hz, 1H), 2.52 (t, J=7.3 Hz, 2H), 1.64 (d, J=6.9 Hz, 3H),1.64-1.53 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

SO3-104 (14f)

(R)-2-(4-Propyl-phenoxy)-propanoic acid (SO3-104) (14f): NaH (60%suspension, 130 mg, 3.27 mmol) was added to a solution of(R)-bromopropionoc acid (500 mg, 3.27 mmol) in THF (10 ml). In aseparate vessel NaH (60% suspension, 260 mg, 6.54 mmol) was added to asolution of p-cresol (900 mg, 6.54 mmol). The phenolate solution wascalculated into the 2-bromopropionate solution, and stirred at roomtemperature for 0.5 h. The reaction was quenched with NaOH solution (20ml, 2 M NaOH), and kept stirring at room temperature for another hour.The reaction was acidified with HCl (2M) up to pH=1, and extracted withEt₂O (3×25 ml). The Et₂O extract was dried over anhydrous (MgSO₄) andconcentrated. The residue was purified by column chromatography to yieldthe acid SO3-104 14f as a viscous yellow liquid. (640 mg, 94%). ¹H NMR(400 MHz, CDCl₃) δ 7.09 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 4.76(q, J=6.9 Hz, 1H), 2.52 (t, J=7.3 Hz, 2H), 1.65 (d, J=6.9 Hz, 3H),1.64-1.55 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

SO2-142 (15a)

2-(p-tolyloxy)propanoyl chloride (SO2-142): This compound wassynthesized using the same protocol for SO1-140 5a except using2-p-tolyloxy-propionic acid (14a) (300 mg, 1.66 mmol), SOCl₂ (10 ml) andbenzene (10 ml). SO2-142 (15a) was isolated as yellow liquid (317 mg,96%). ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.6Hz, 2H), 4.92 (q, J=6.8 Hz, 1H), 2.30 (s, 3H), 1.74 (d, J=6.8 Hz, 3H).

SO3-015 (15b)

(S)-2-(p-tolyloxy)propanoyl chloride (SO3-015) (15b): This compound wassynthesized using the same protocol for SO1-140 5a except using(S)-2-(p-tolyloxy)propanoic acid (130 mg, 0.72 mmol), SOCl₂ (10 ml) andbenzene (10 ml). SO3-015 15b was isolated as yellow liquid (133 mg,93%). ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=8.5 Hz, 2H), 6.77 (d, J=8.6Hz, 2H), 4.90 (q, J=6.8 Hz, 1H), 2.29 (s, 3H), 1.73 (d, J=6.8 Hz, 3H).

SO3-063 (15c)

(R)-2-(p-tolyloxy)propanoyl chloride (SO3-015) (15c): This compound wassynthesized using the same protocol for SO1-140 5a except using(R)-2-(p-tolyloxy)propanoic acid (14c) (130 mg, 0.72 mmol), SOCl₂ (10ml) and benzene (10 ml). SO3-063 15c was isolated as yellow liquid (139mg, 97%). ¹H NMR (400 MHz, CDCl₃) δ 7.10 (d, J=8.5 Hz, 2H), 6.78 (d,J=8.6 Hz, 2H), 4.91 (q, J=6.8 Hz, 1H), 2.29 (s, 3H), 1.73 (d, J=6.8 Hz,3H).

SO3-105 (15d)

2-(4-Propylphenoxy)propanoyl chloride (SO3-105) (15d): This compound wassynthesized using the same protocol for SO1-140 5a except using2-(4-propyl-phenoxy)-propionic acid (14d) (150 mg, 0.72 mmol), SOCl₂ (10ml) and benzene (10 ml). SO3-105 15d was isolated as greenish yellowliquid (157 mg, 96%). ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J=8.6 Hz, 2H),6.80 (d, J=8.6 Hz, 2H), 4.92 (q, J=6.8 Hz, 1H), 2.54 (t, J=7.4 Hz, 2H),1.74 (d, J=6.8 Hz, 2H), 1.71-1.51 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

SO3-108 (15e)

(S)-2-(4-Propylphenoxy)propanoyl chloride (SO3-108) (15e): This compoundwas synthesized using the same protocol for SO1-140 5a except using(S)-2-(4-propyl-phenoxy)-propionic acid (14e) (300 mg, 1.44 mmol), SOCl₂(10 ml) and benzene (10 ml). SO3-108 15e was isolated as yellow liquid(304 mg, 93%). ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J=8.6 Hz, 1H), 6.80(d, J=8.6 Hz, 1H), 4.92 (q, J=6.8 Hz, 1H), 2.53 (t, J=7.4 Hz, 2H), 1.74(d, J=6.8 Hz, 3H), 1.67-1.51 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

SO3-107 (15f)

(R)-2-(4-Propyl-phenoxy)-propionyl chloride (SO3-107) (15f): Thiscompound was synthesized using the same protocol for SO1-140 5a exceptusing (R)-2-(4-propyl-phenoxy)-propionic acid (14f) (300 mg, 1.44 mmol),SOCl₂ (10 ml) and benzene (10 ml). SO3-107 15f was isolated as yellowliquid (311 mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J=8.7 Hz, 2H),6.80 (d, J=8.7 Hz, 2H), 4.91 (q, J=6.8 Hz, 1H), 2.53 (t, J=7.3 Hz, 2H),1.74 (d, J=6.8 Hz, 3H), 1.68-1.53 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

SO2-026 (22a)

3-(4-(Trifluoromethyl)phenyl)propanoyl chloride (SO2-026) (22a): Thiscompound was synthesized using the same protocol for SO1-140 exceptusing 3-(4-(trifluoromethyl)phenyl)propanoic acid (700 mg, 3.21 mmol),SOCl₂ (10 ml) and benzene (10 ml). SO2-026 22a was isolated as yellowliquid (714 mg, 94%). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J=8.1 Hz, 2H),7.33 (d, J=8.0 Hz, 2H), 3.24 (t, J=7.3 Hz, 2H), 3.08 (t, J=7.3 Hz, 2H).

SO3-028 (22b)

Benzofuran-2-carbonyl chloride (SO3-028) (22b): This compound wassynthesized using the same protocol for SO1-140 except usingbenzofuran-2-carbonic acid (300 mg, 1.85 mmol), SOCl₂ (5 ml) and benzene(5 ml). SO3-028 22b was isolated as yellow liquid (314 mg, 94%). ¹H NMR(400 MHz, CDCl₃) δ 7.85 (d, J=0.9 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H),7.65-7.51 (m, 2H), 7.37 (ddd, J=8.1, 6.8, 1.3 Hz, 1H).

SO2-066 (19)

N-Isopropyl-2-chloro-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamideSO2-066 (19): To a solution of 10c (80 mg, 0.36 mmol) and triethyl amine970 mg, 0.72 mmol) in THF (4 ml) was added chloroacetyl chloride (50 mg,0.44 mmol) in THF (1 ml) slowly. The reaction was monitored by TLC andcompleted in 15 min. THF was evaporated and the residue was dissolved inEtOAc (15 ml) and washed with 4M HCl (2×15 ml) and water (2×15 ml).Organic solvent was dried (MgSO₄) and evaporated. The compound waspurified by column chromatography (EtOAc:hexane gradient elution) toobtain SO2-066 (19) as a viscous colorless liquid (84 mg, 80%).

HPLC 100% (R_(t)=5.54 min, 60% CH₃CN in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 8.09-8.00 (m, 2H), 7.53-7.41 (m, 3H), 4.79 (s, 2H),4.70 (s, 2H) [δ 4.79 minor isomer shown]), 4.33-4.24 (m, 1H) [δ4.90-4.79 minor isomer shown]), 4.20 (s, 2H), 1.34 (d, J=6.6 Hz, 6H), [δ1.15 minor isomer shown]). LC-MS (ESI+) m/z 294.10 (M+H)⁺316.09 (M+Na)⁺;HRMS (ESI+ve) m/z calculated for C₁₄H₁₇N₃O₃ (M+H)⁺294.1004. found294.1005.

SO2-059 (31)

tert-Butyl 4-hydroxybenzoate (SO2-059) (31): Hydroxy benzoic acid (1.50g, 10.86 mmol), tert-butanol (13.34 g, 18 mmol), DBU (0.19 ml, 1.20mmol) and DCC (2.5 g, 12.00 mmol) were mixed in DCM (40 ml) andvigorously stirred for 18 h. After evaporation to dryness, DCM (50 ml)was added to the residue and the resulting heterogeneous solution wasfiltered. The solution was washed with sat. K₂CO₃ (2×50 ml) and sat.NaCl (50 ml). The solvent was dried (MgSO₄) and evaporated and purifiedby column chromatography (EtOAc:hexane gradient elution) to obtainSO2-059 31 as a crystalline white compound. (1.1 g, 55%). ¹H NMR (400MHz, cdcl₃) δ 7.89 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 5.29 (s,1H), 1.57 (s, 9H).

SO1-143 (1)

N-Isopropyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO1-143) (1): To a solution ofisopropyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (10a) (180 mg,0.81 mmol) and triethyl amine (160 mg, 1.6 mmol) in THF (15 ml) at roomtemperature was added p-tolyloxy-acetyl chloride (5a) (300 mg, 0.17mmol) in THF (3 ml) dropwise. As the acyl chloride was added, aprecipitate was formed and the reaction was completed in 10 min. The THFwas evaporated and the residue was dissolved in EtOAc (20 ml), washedwith 4M HCl (2×15 ml) and water (15 ml). Organic phase was dried (MgSO₄)and evaporated and the product obtained was purified by columnchromatography (Sift, EtOAc:hexane gradient elution) to obtain 1 as awhite solid (270 mg, 88%). M.p. 142.1-143.4° C.

HPLC 100% (R_(t)=11.8 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d,J=8.0 Hz, 2H [δ 7.93 minor isomer shown]), 7.30-7.25 (m, 2H), 7.09 (d,J=8.3 Hz, 2H [δ 7.05 minor isomer shown]), 6.87 (d, J=8.5 Hz, 1H [δ 6.82minor isomer shown]), 4.78 (s, 1H [δ 4.84 minor isomer shown]), 4.70 (s,1H [δ 4.83 minor isomer shown]), 4.45-4.39 (m, 1H), 2.42 (s, 1H [δ 2.41minor isomer shown]), 2.28 (s, 1H [δ 2.25 minor isomer shown]), 1.30 (d,J=6.6 Hz, 6H [δ 1.15 minor isomer shown]);

¹H NMR (400 MHz, d₆-DMSO) δ 7.84 (d, J=8.2 Hz, 2H [δ 7.87 minor isomershown]), 7.36 (d, J=7.9 Hz, 2H [δ 7.37 minor isomer]), 7.01 (d, J=8.6Hz, 2H), 6.78 (d, J=8.6 Hz, 2H [δ 6.75 minor isomer shown]), 4.88 (s, 2H[δ 4.98 minor isomer shown]), 4.71 (s, 2H [δ 4.82 minor isomer shown]),4.31-4.21 (m, 1H [δ 4.62-4.52 minor isomer shown]), 2.37 (s, 3H), 2.18(s, 3H), 1.26 (d, J=6.6 Hz, 6H [δ 1.06 minor isomer shown]); ¹³C NMR(100 MHz, CDCl₃) δ 176.40 [δ 176.54 minor isomer shown], 168.51 [δ168.56 minor isomer shown], 156.01 [δ 155.81 minor isomer shown],141.68, 131.23 [δ 131.25 minor isomer shown], 130.29 [δ 130.24 minorisomer shown], 129.68 [δ 129.84 minor isomer shown], 127.65, 124.08114.68 [δ 114.64 minor isomer shown], 67.99 [δ 68.74 minor isomershown], 48.96 [δ 46.96 minor isomer shown], 37.20 [δ 38.40 minor isomershown], 21.49 [δ 19.97 minor isomer shown], 20.81, 20.73.

Anal. Calcd for C₂₂H₂₅N₃O₃: C, 69.64; H, 6.64; N, 11.07. Found: C,69.51; H, 6.74; N, 11.13.

LC-MS (ESI+) m/z 380.24 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₆N₃O₃ (M+H)⁺380.1969. found 380.1966.

SO1-176 (11a)

N-Isopropyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-2-(4-(trifluoromethyl)phenoxy)acetamide(SO1-176) (11a): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-trifluoromethyl-phenoxy)-acetylchloride (5b) (190 mg, 0.78 mmol) andisopropyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (10a) (120 mg,0.52 mmol) and triethyl amine (100 mg, 1 mmol). The compound 11a(SO1-176) was isolated as a white solid (190 mg, 87%). M.p. 76.6-78.5°C.

HPLC 99.87% (R_(t)=14.8 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d,J=8.1 Hz, 2H), 7.54 (d, J=8.7 Hz, 2H [δ 7.51 minor isomer shown]),7.27-7.23 (d, J=7.9 Hz, 2H [δ 7.29 minor isomer shown]), 7.04 (d, J=8.5Hz, 2H), 4.88 (s, 2H [δ 4.94 minor isomer shown]), 4.71 (s, 2H [δ 4.76minor isomer shown]), 4.38-4.34 (m, 1H), 2.41 (s, 3H [δ 2.43 minorisomer shown]), 1.32 (d, J=6.6 Hz, 6H [δ 1.16 minor isomer shown]); ¹³CNMR (100 MHz, CDCl₃) δ 176.16 [δ 176.23 minor isomer shown], 168.57 [δ167.84 minor isomer shown], 167.80 [δ 167.87 minor isomer shown],160.48, 141.86 [δ 142.43 minor isomer shown], 129.73 127.58, 127.29 (q,J=3.67 Hz), 124.47 (q, J=270 Hz), 124.11 (q, J=32.5 Hz), 123.88 [δ123.86 minor isomer shown], 114.96 [δ 114.90 minor isomer shown],114.82, 67.48 [δ 67.90 minor isomer shown], 49.00 [δ 47.05 minor isomershown], 37.23 [δ 38.35 minor isomer shown], 21.45 [δ 19.96 minor isomershown], 21.81; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.02 [δ −62.06 minor isomershown].

LC-MS (ESI+) m/z 434.18 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₃F₃N₃O₃ (M+H)⁺434.1686. found 434.1711.

SO1-171 (11b)

N-Isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-2-(4-(trifluoromethyl)phenoxy)acetamide(SO1-171) (11b): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-trifluoromethyl-phenoxy)-acetylchloride (5b) (240 mg, 0.92 mmol) andisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (100 mg,0.46 mmol) and triethyl amine (90 mg, 0.92 mmol). The compound 11b(SO1-171) was isolated as a white solid (170 mg, 89%). M.p. 97.9-99.3°C.

HPLC 100% (R_(t)=10.4 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 2.5:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.00(dd, J=8.0 Hz, 1.6 Hz, 2H), 7.62-7.37 (m, 3H), 7.05 (d, J=8.8 Hz, 2H),4.88 (s, 2H [δ 4.94 minor isomer shown]), 4.72 (s, 2H [δ 4.79 minorisomer shown]), 4.39-4.35 (m, 1H), 1.32 (d, J=6.6 Hz, 6H [δ 1.16 minorisomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.36 [δ 176.47 minor isomershown], 168.58 [δ 168.54 minor isomer shown], 167.66 [δ 166.71 minorisomer shown], 160.50 [δ 160.47 minor isomer shown], 131.47 [δ 131.92minor isomer shown], 130.34, 129.00 [δ 129.20 minor isomer shown],127.65, 127.29 (q, J=3.74 Hz), 126.78, 126.17, 124.46 (q, J=270 Hz),124.14 (q, J=32.7 Hz), 114.97 [δ 114.75 minor isomer shown], 114.90,67.56 [δ 68.07 minor isomer shown], 65.33, 48.96 [δ 47.07 minor isomershown], 37.21 [δ 38.41 minor isomer shown], 21.48 [δ 19.98 minor isomershown]; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.03 [δ −62.07 minor isomer shown].

LC-MS (ESI+) m/z 420.16 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₁F₃N₃O₃ (M+H)⁺420.1530. found 420.1547.

SO1-170 (11c)

N-Isopropyl-2-(4-(trifluoromethyl)phenoxy)-N-((3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO1-170) (11c): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-trifluoromethyl-phenoxy)-acetylchloride (5b) (180 mg, 0.70 mmol) andisopropyl-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine(10b) (100 mg, 0.35 mmol) and triethyl amine (71 mg, 0.70 mmol). Thecompound 11c (SO1-170) was isolated as a white solid (160 mg, 92%). M.p.92-94.5° C.

HPLC 95% (R_(t)=19.0 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d,J=8.3 Hz, 2H), 7.72 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H [δ 7.49minor isomer shown]), 7.04 (d, J=8.7 Hz, 2H [δ 6.97 minor isomershown]), 4.88 (s, 2H [δ 4.91 minor isomer shown]), 4.72 (s, 2H [δ 4.84minor isomer shown]), 4.42-4.38 (m, 1H), 1.34 (d, J=6.6 Hz, 6H [δ 1.17minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.91, 167.87 [δ167.60 minor isomer shown], 160.42 [δ 160.02 minor isomer shown], 133.18(q, J=33 Hz), 130.16, 128.01 [δ 128.12 minor isomer shown], 127.32 (q,J=3.59 Hz), 126.03 (q, J=3.81 Hz), 124.41 (q, J=270 Hz), 124.23 (q,J=32.59 Hz), 123.94 (q, J=270 Hz), 114.94 [δ 114.90 minor isomer shown],114.83, 67.51 [δ 64.80 minor isomer shown], 49.08, 37.30, 29.94, 21.50[δ 19.97 minor isomer shown]; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.07 [δ−62.02 minor isomer shown], −62.13 [δ −62.14 minor isomer shown], −62.45[δ −62.52 minor isomer shown],

LC-MS (ESI+) m/z 488.14 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₀F₆N₃O₃ (M+H)⁺488.1403. found 488.1419.

SO1-169 (11d)

N-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-N-isopropyl-2-(4-(trifluoromethyl)phenoxy)acetamide(SO1-169) (11d): This compound was synthesized using the same protocolfor 1 (SO1-143) 1 except using 2-(4-trifluoromethyl-phenoxy)-acetylchloride (5b) (200 mg, 0.80 mmol) and[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-isopropyl-amine (10d)(100 mg, 0.4 mmol) and triethyl amine (80 mg, 0.79 mmol). The compound11d (SO1-169) was isolated as a white solid (140 mg, 85%). M.p.111.4-113.9° C.

HPLC 100% (R_(t)=16.5 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3.4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.93(d, J=8.6 Hz, 2H), 7.54 (d, J=8.7 Hz, 2H [δ 7.50 minor isomer shown]),7.43 (d, J=8.6 Hz, 2H [δ 7.46 minor isomer shown]), 7.04 (d, J=8.6 Hz,2H [δ 6.99 minor isomer shown]), 4.88 (s, 2H [δ 4.92 minor isomershown]), 4.70 (s, 2H [δ 4.80 minor isomer shown]), 4.41-4.35 (m, 1H),1.32 (d, J=6.6 Hz, 6H [δ 1.16 minor isomer shown]); ¹³C NMR (100 MHz,CDCl₃) δ 176.60 [δ 176.74 minor isomer shown], 167.81 [δ 167.70 minorisomer shown], 160.46 [δ 160.40 minor isomer shown], 137.61, 129.54,129.35, 128.96, 127.31 (q, J=3.7 Hz), 125.28, 124.45 (q, J=270 Hz),124.17 (q, J=32 Hz), 114.95 [δ 114.87 minor isomer shown], 68.25, 67.54[δ 68.25 minor isomer shown], 49.00 [δ 47.16 minor isomer shown], 38.50,37.25 [δ 38.50 minor isomer shown], 21.50, [δ 19.98 minor isomer shown];¹⁹F NMR (376 MHz, CDCl₃) δ −62.03 [δ −62.08 minor isomer shown].

LC-MS (ESI+) m/z 454.12 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₀ClF₃N₃O₃ (M+H)⁺454.1140. found 454.1149.

SO2-002 (11e)

2-(4-Chlorophenoxy)-N-isopropyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-002) (11e): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-chlorophenoxy)acetyl chloride (5d)(130 mg, 0.65 mmol) andisopropyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (10a) (100 mg,0.43 mmol) and triethyl amine (90 mg, 0.86 mmol). The compound 11e(SO2-002) was obtained as a white solid (150 mg, 88%). M.p. 133.1-136.5°C.

HPLC 98.5% (R_(t)=12.5 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d,J=8.3 Hz, 2H [δ 7.91 minor isomer shown]), 7.26 (J=8.6 Hz, 2H [δ 7.29minor isomer shown]), 7.23 (J=9.0 Hz, 2H [δ 7.20 minor isomer shown]),6.86 (d, J=9.0 Hz, 2H [δ 6.87 minor isomer shown]), 4.81 (s, 2H [δ 4.86minor isomer shown]), 4.70 (s, 2H [δ 4.79 minor isomer shown]),4.42-4.35 (m, 1H), 2.41 (s, 3H), 1.30 (d, J=6.6 Hz, 6H [δ 1.15 minorisomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.22 [δ 176.34 minor isomershown], 168.57, 168.01, 156.75, 141.75 [δ 142.36 minor isomer shown],129.90, 129.74 [δ 129.72 minor isomer shown], 129.67, 127.61 [δ 126.90minor isomer shown], 123.98 [δ 123.42 minor isomer shown], 116.24 [δ116.17 minor isomer shown], 67.95 [δ 68.47 minor isomer shown], 48.93 [δ46.97 minor isomer shown], 37.17 [δ 38.37 minor isomer shown], 21.47 [δ19.98 minor isomer shown], 21.82.

LC-MS (ESI+) m/z 400.15 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₃ClN₃O₃ (M+H)⁺400.1423. found 400.1448.

SO1-180 (11f)

2-(4-Chlorophenoxy)-N-isopropyl-N-((3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO1-180) (11f): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-chlorophenoxy)acetyl chloride (5d)(110 mg, 0.53 mmol) andisopropyl-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine(10b) (100 mg, 0.35 mmol) and triethyl amine (71 mg, 0.70 mmol). Thecompound 11f (SO1-180) was isolated as a white solid (130 mg, 81%). M.p.106.4-108.9° C.

HPLC 99.8% (R_(t)=17.1 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d,J=8.1 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 7.23 (d, J=9.0 Hz, 2H [δ 7.18minor isomer shown]), 6.91 (d, J=9.0 Hz, 2H [δ 6.83 minor isomershown]), 4.81 (s, 2H [δ 4.85 minor isomer shown]), 4.70 (s, 2H [δ 4.83minor isomer shown]), 4.45-4.39 (m, 1H), 1.32 (d, J=6.6 Hz, 6H [δ 1.16minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 177.00, 168.16 [δ167.64 minor isomer shown], 156.68, 133.11 (q, J=32.6 Hz), 129.76 [δ130.18 minor isomer shown], 128.04, 126.96, 126.08 (q, J=3.8 Hz), 123.96(q, J=270 Hz), 116.20 [δ 116.08 minor isomer shown], 67.91 [δ 68.88minor isomer shown], 49.01 [δ 47.09 minor isomer shown], 37.24 [δ 38.52minor isomer shown], 21.50 [δ 19.88 minor isomer shown]; ¹⁹F NMR (376MHz, CDCl₃) δ −63.40 [δ −63.46 minor isomer shown]. LC-MS (ESI+) m/z454.11 (M+H)⁺; HRMS (ESI+ve) m/z calculated for C₂₁H₂₀ClF₃N₃O₃(M+H)⁺454.1140. found 454.1142.

SO1-179 (11g)

2-(4-Chlorophenoxy)-N-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-N-isopropylacetamide(SO1-179) (11g): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-chlorophenoxy)acetyl chloride (5d)(120 mg, 0.60 mmol) and[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-isopropyl-amine (10d)(100 mg, 0.40 mmol) and triethyl amine (80 mg, 0.79 mmol). The compound11g (SO1-179) was obtained as a white solid (140 mg, 91%). M.p.133.4-135.8° C.

HPLC 99.9% (R_(t)=15.5 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4.4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.92(d, J=8.7 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.23 (d, J=9.0 Hz, 2H [δ 7.19minor isomer shown]), 6.91 (d, J=9.1 Hz, 2H [δ 6.84 minor isomershown]), 4.80 (s, 2H [δ 4.83 minor isomer shown]), 4.69 (s, 2H [δ 4.81minor isomer shown]), 4.40-4.37 (m, 1H), 1.30 (d, J=6.6 Hz, 6H [δ 1.15minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.66 [δ 176.83 minorisomer shown], 168.10 [δ 167.78 minor isomer shown], 156.69, 137.56,129.75, 129.36 [δ 129.54 minor isomer shown], 128.99, 126.93, 125.29,116.20 [δ 116.11 minor isomer shown], 67.90 [δ 68.68 minor isomershown], 48.96, 37.20, 21.49 [δ 19.98 minor isomer shown].

LC-MS (ESI+) m/z 420.08 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₂₀Cl₂N₃O₃ (M+H)⁺420.0876. found 420.0891.

SO1-181 (11h)

2-(4-Chlorophenoxy)-N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO1-181) (11h): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-chlorophenoxy)acetyl chloride (5d)(200 mg, 0.96 mmol) andisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (120 mg,0.48 mmol) and triethyl amine (100 mg, 0.95 mmol). The compound 11h(SO1-181) was obtained as a white solid (150 mg, 82%). M.p. 108.3-109.5°C.

HPLC 99.8% (R_(t)=9.5 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.99(dd, J=7.9, 1.7 Hz, 2H [δ 8.02 minor isomer shown]), 7.56-7.41 (m, 3H),7.23 (d, J=9.0 Hz, 2H [δ 7.19 minor isomer shown]), 6.91 (d, J=9.0 Hz,2H [δ 6.87 minor isomer shown]), 4.80 (s, 2H [δ 4.85 minor isomershown]), 4.70 (s, 2H), 4.43-4.36 (m, 1H), 1.30 (d, J=6.6 Hz, 6H [δ 1.15minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.42, 168.56, 168.08,156.73, 131.44 [δ 131.87 minor isomer shown], 129.75 [δ 129.68 minorisomer shown], 129.75 [δ 129.02 minor isomer shown], 127.69, 126.91,126.79, 116.23 [δ 116.16 minor isomer shown], 67.92 [δ 68.52 minorisomer shown], 48.97 [δ 47.07 minor isomer shown], 37.19 [δ 38.43 minorisomer shown], 21.47 [δ 19.98 minor isomer shown].

LC-MS (ESI+) m/z 386.14 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₂₁ClN₃O₃ (M+H)⁺386.1266. found 386.1269.

SO1-160 (11i)

N-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-N-isopropyl-2-(p-tolyloxy)acetamide(SO1-160) (11i): This compound was synthesized using the same protocolfor 1 (SO1-143) except using p-tolyloxy-acetyl chloride (5a) (110 mg,0.60 mmol) and[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-isopropyl-amine (10d)(100 mg, 0.4 mmol) and triethyl amine (80 mg, 0.80 mmol). The compound11i (SO1-160) was isolated as a white solid (140 mg, 85%). M.p.133.5-134.3° C.

HPLC 99.7% (R_(t)=21.0 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3.6:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.95(d, J=8.6 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H [δ 7.45 minor isomer shown]),7.08 (d, J=8.3 Hz, 2H [δ 7.03 minor isomer shown]), 6.87 (d, J=8.6 Hz,2H [δ 6.79 minor isomer shown]), 4.78 (s, 2H [δ 4.86 minor isomershown]), 4.69 (s, 2H [δ 4.81 minor isomer shown]), 4.46-4.40 (m, 1H),2.28 (s, 3H [δ 2.25 minor isomer shown]), 1.30 (d, J=6.6 Hz, 6H [δ 1.15minor isomer shown]); ¹³C NMR (101 MHz, CDCl₃) δ 176.85, [δ 176.00 minorisomer shown], 168.56 [δ 167.78 minor isomer shown], 156.26, 137.34,131.26, 130.28 [δ 130.24 minor isomer shown], 129.30 [δ 129.45 minorisomer shown], 129.04, 125.42, 114.67 [δ 114.59 minor isomer shown],67.98 [δ 68.95 minor isomer shown], 48.96 [δ 47.05 minor isomer shown],37.22 [δ 38.48 minor isomer shown], 21.50, 20.74 [δ 19.99 minor isomershown].

LC-MS (ESI+) m/z 400.14 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₃ClN₃O₃ (M+H)⁺400.1423. found 400.1423.

SO2-011 (11j)

N-Isopropyl-2-phenoxy-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-011) (11j): This compound was synthesized using the same protocolfor 1 (SO1-143) except using phenoxyacetyl chloride (5c) (47 mg, 0.27mmol) and isopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c)(50 mg, 0.27 mmol) and triethyl amine (47 mg, 0.46 mmol). The compound11j (SO2-011) was obtained as a white solid (60 mg, 76%). M.p.77.9-79.0° C.

HPLC 94.37% (R_(t)=11.6 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.02(dd, J=8.1, 1.6 Hz, 2H), 7.59-7.40 (m, 3H), 7.36-7.22 (m, 2H), 7.03-6.95(m, 3H), 4.83 (s, 2H [δ 4.88 minor isomer shown]), 4.72 (s, 2H [δ 4.86minor isomer shown]), 4.46-4.40 (m, 1H), 1.31 (d, J=6.6 Hz, 6H [δ 1.16minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.53 [δ 176.65 minorisomer shown], 168.72 [δ 168.80 minor isomer shown], 168.53, 158.01 [δ157.85 minor isomer shown], 156.40 131.44 [δ 131.81 minor isomer shown],129.88 [δ 129.82 minor isomer shown], 129.79, 129.00 [δ 129.17 minorisomer shown], 127.73 [δ 127.69 minor isomer shown], 127.04, 126.78,122.00, 116.21, 114.86 [δ 114.81 minor isomer shown], 67.66 [δ 68.34minor isomer shown], 49.09 [δ 47.12 minor isomer shown], 37.28 [δ 38.45minor isomer shown], 21.43 [δ 19.95 minor isomer shown].

LC-MS (ESI+) m/z 352.17 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₂₂N₃O₃ (M+H)⁺352.1656. found 352.1662.

SO2-006 (11k)

N-Isopropyl-2-phenoxy-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-006) (11k): This compound was synthesized using the same protocolfor 1 (SO1-143) except using phenoxyacetyl chloride (5c) (80 mg, 0.46mmol) and isopropyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (10a)(89 mg, 0.39 mmol) and triethyl amine (78 mg, 0.77 mmol). The compound11k (SO2-006) was obtained as a white solid (100 mg, 78%). M.p.97.8-99.5° C.

HPLC 99.8% (R_(t)=8.5 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d,J=8.2 Hz, 2H [δ 7.93 minor isomer shown]), 7.34-7.22 (m, 4H), 7.00-6.94(m, 3H), 4.82 (s, 2H [δ 4.87 minor isomer shown]), 4.71 (s, 2H [δ 4.83minor isomer shown]), 4.45-4.39 (m, 1H), 2.41 (s, 3H [δ 2.42 minorisomer shown]), 1.30 (d, J=6.6 Hz, 6H [δ 1.15 minor isomer shown]); ¹³CNMR (100 MHz, CDCl₃) δ 176.49 [δ 176.50 minor isomer shown], 168.34 [δ168.55 minor isomer shown], 141.68 [δ 142.23 minor isomer shown], 129.86[δ 129.81 minor isomer shown], 129.68, 127.65, 124.01, 121.95, 114.86 [δ114.83 minor isomer shown], 68.49, 67.81 [δ 68.49 minor isomer shown],48.96 [δ 46.89 minor isomer shown], 37.21 [δ 38.37 minor isomer shown],21.48 [δ 19.98 minor isomer shown].

LC-MS (ESI+) m/z 366.19 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₄N₃O₃ (M+H)⁺366.1812. found 366.1816.

SO2-010 (11l)

N-Isopropyl-2-phenoxy-N-((3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-010) (11l): This compound was synthesized using the same protocolfor 1 (SO1-143) except using phenoxyacetyl chloride (5c) (70 mg, 0.42mmol) andisopropyl-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine(10b) (80 mg, 0.28 mmol) and triethyl amine (57 mg, 0.56 mmol). Thecompound 11l (SO2-010) was obtained as a white solid (95 mg, 81%). M.p.122.8-123.8° C.

HPLC 100% (R_(t)=11.6 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4.5:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.13(d, J=8.1 Hz, 2H [δ 8.15 minor isomer shown]), 7.72 (d, J=8.2 Hz, 2H [δ7.75 minor isomer shown]), 7.35-7.26 (m, 2H), 7.03-6.94 (m, 3H [δ 6.90minor isomer shown]), 4.83 (s, 2H [δ 4.89 minor isomer shown]), 4.72 (s,2H [δ 4.86 minor isomer shown]), 4.48-4.43 (m, 1H), 1.32 (d, J=6.6 Hz,6H [δ 1.16 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 177.15 [δ177.39 minor isomer shown], 168.45 [δ 167.58 minor isomer shown],158.04, 133.07 (q, J=32.6 Hz), 130.29 [δ 130.27 minor isomer shown],129.87 [δ 129.83 minor isomer shown], 128.09, 125.97 (q, J=3.7 Hz),123.99 (q, J=271 Hz), 121.99 [δ 122.07 minor isomer shown], 114.83 [δ114.75 minor isomer shown], 67.75 [δ 68.75 minor isomer shown], 49.01 [δ47.05 minor isomer shown], 37.27 [δ 38.58 minor isomer shown], 21.50 [δ19.98 minor isomer shown]; ¹⁹F NMR (376 MHz, CDCl₃) δ −63.37, [δ −63.43minor isomer shown].

LC-MS (ESI+) m/z 420.15 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₁F₃N₃O₃ (M+H)⁺420.1530. found 420.1530.

SO1-172 (11m)

N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO1-172) (11m): This compound was synthesized using the same protocolfor 1 (SO1-143) except using p-tolyloxy-acetyl chloride (5a) (130 mg,0.69 mmol) and isopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine(10c) (100 mg, 0.46 mmol) and triethyl amine (93 mg, 0.92 mmol). Thecompound 11m (SO1-172) was isolated as a white solid (150 mg, 91%). M.p.134.7-136.5° C.

HPLC 97% (R_(t)=8.5 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹H NMRshowed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.02 (dd,J=8.0, 1.6 Hz, 2H), 7.55-7.41 (m, 3H), 7.08 (d, J=8.3 Hz, 2H [δ 7.04minor isomer shown]), 6.87 (d, J=8.6 Hz, 2H [δ 6.81 minor isomershown]), 4.78 (s, 2H [δ 4.85 minor isomer shown]), 4.71 (s, 2H [δ 4.83minor isomer shown]), 4.45-4.40 (m, 1H), 2.28 (s, 3H [δ 2.25 minorisomer shown]), 1.30 (d, J=6.6 Hz, 6H [δ 1.15 minor isomer shown]); ¹³CNMR (100 MHz, CDCl₃) δ 176.62, 168.53, 156.00, 131.74, 131.37 [δ 131.74minor isomer shown], 131.22 [δ 131.25 minor isomer shown], 130.28 [δ130.24 minor isomer shown], 128.97 [δ 129.13 minor isomer shown],127.73, 126.89, 114.68 [δ 114.62 minor isomer shown], 67.97 [δ 68.75minor isomer shown], 48.93 [δ 46.94 minor isomer shown], 37.20 [δ 38.44minor isomer shown], 21.48, [δ 19.98 minor isomer shown], 20.74.

LC-MS (ESI+) m/z 366.18 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₄N₃O₃ (M+H)⁺366.1812. found 366.1828.

SO1-159 (11n)

N-Isopropyl-2-(p-tolyloxy)-N-((3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO1-159) (11n): This compound was synthesized using the same protocolfor 1 (SO1-143) except using p-tolyloxy-acetyl chloride (5a) (130 mg,0.70 mmol) andisopropyl-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine(10b) (100 mg, 0.35 mmol) and triethyl amine (71 mg, 0.70 mmol). Thecompound 11n (SO1-159) was isolated as a white solid (130 mg, 84%). mp146.9-148.6° C.

HPLC 99% (R_(t)=16.1 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d,J=8.1 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.3 Hz, 2H [δ 7.02minor isomer shown]), 6.87 (d, J=8.6 Hz, 2H [δ 6.77 minor isomershown]), 4.79 (s, 2H [δ 4.89 minor isomer shown]), 4.70 (s, 2H [δ 4.81minor isomer shown]), 4.48-4.42 (m, 1H), 2.28 (s, 3H [δ 2.23 minorisomer shown]), 1.31 (d, J=6.6 Hz, 6H [δ 1.16 minor isomer shown]); ¹³CNMR (100 MHz, CDCl₃) δ 177.20 [δ 178.43 minor isomer shown], 168.62, [δ167.54 minor isomer shown], 155.98 [δ 155.73 minor isomer shown], 131.27[δ 131.37 minor isomer shown], 130.29 [δ 130.24 minor isomer shown],128.09, 126.88 (q, J=28 Hz), 125.97 (q, J=4.1 Hz), 125.68 (q, J=262.26Hz), 114.65 [δ 114.54 minor isomer shown], 67.94 [δ 68.85 minor isomershown], 48.97, 37.26, 21.50, 20.74 [δ 19.62 minor isomer shown]; ¹⁹F NMR(376 MHz, CDCl₃) δ −63.39 [δ −63.45 minor isomer shown].

LC-MS (ESI+) m/z 434.18 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₃F₃N₃O₃ (M+H)⁺434.1686. found 434.1693.

SO2-058 (11o)

N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-2-(m-tolyloxy)acetamide(SO2-058) (110): This compound was synthesized using the same protocolfor 1 (SO1-143) except using m-tolyloxy-acetyl chloride (5h) (76 mg,0.41 mmol) and isopropyl-(3-phenyl-[1,2,4]oxadiazol-5-ylmethyl)-amine(10c) (60 mg, 0.30 mmol) and triethyl amine (60 mg, 0.60 mmol). Thecompound 110 (SO2-058) was obtained as a colorless viscous compound (83mg, 76%).

HPLC 98.5% (R_(t)=8.6 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.01(dd, J=8.0, 1.5 Hz, 2H [δ 8.08 minor isomer shown]), 7.58-7.37 (m, 4H),7.17 (t, J=7.6 Hz, 1H), 6.87-6.65 (m, 2H), 4.79 (s, 2H [δ 4.85 minorisomer shown]), 4.71 (s, 2H [δ 4.84 minor isomer shown]), 4.46-4.40 (m,1H), 2.31 (s, 3H [δ 2.25 minor isomer shown]), 1.31 (d, J=6.6 Hz, 6H [δ1.16 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.58, 168.43 [δ168.56 minor isomer shown], 158.09, 139.99, 131.74, 131.36 [δ 131.74minor isomer shown], 129.58 [δ 129.53 minor isomer shown], 128.96 [δ129.13 minor isomer shown], 127.72, 126.90, 122.80 [δ 122.84 minorisomer shown], 115.64 [δ 115.74 minor isomer shown], 111.70 [δ 111.46minor isomer shown], 67.79 [δ 68.59 minor isomer shown], 48.97 [δ 46.97minor isomer shown], 37.22 [δ 38.52 minor isomer shown], 21.49 [δ 19.98minor isomer shown], 21.76.

LC-MS (ESI+) m/z 366.19 HRMS (ESI+ve) m/z calculated for C₂₁H₂₄N₃O₃(M+H)⁺366.1812. found 366.1817.

SO2-073 (11p)

N-Isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-2-(o-tolyloxy)acetamide(SO2-073) (11p): This compound was synthesized using the same protocolfor 1 (SO1-143) except using o-tolyloxy-acetyl chloride (5i) (54 mg,0.28 mmol) and isopropyl-(3-phenyl-[1,2,4]oxadiazol-5-ylmethyl)-amine(10c) (50 mg, 0.23 mmol) and triethyl amine (57 mg, 0.56 mmol). Thecompound SO2-073 11p was obtained as a colorless viscos compound (71 mg,85%). M.p. 129.1-130° C.

HPLC 98.0% (R_(t)=9.5 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.95(dd, J=7.9, 1.6 Hz, 2H), 7.47-7.33 (m, 3H), 7.11-7.03 (m, 1H), 6.86-6.78(m, 2H), 4.75 (s, 2H [δ 4.81 minor isomer shown]), 4.65 (s, 2H),4.48-4.38 (m, 1H), 2.22 (s, 3H [δ 2.14 minor isomer shown]), 1.24 (d,J=6.6 Hz, 6H [δ 1.09 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ176.68, 176.57 [δ 176.68 minor isomer shown], 168.57, 168.50, 156.23,131.38 [δ 131.77 minor isomer shown], 131.18, 128.98 [δ 129.15 minorisomer shown], 127.73, 127.25, 126.87, 126.84, 121.61 [δ 121.69 minorisomer shown], 111.28 [δ 111.63 minor isomer shown], 68.01 [δ 68.86minor isomer shown], 48.94, 48.90, 37.22 [δ 38.26 minor isomer shown],21.51 [δ 20.07 minor isomer shown], 16.62.

LC-MS (ESI+) m/z 366.14 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₄N₃O₃ (M+H)⁺366.1812. found 366.1821.

SO2-045 (11q)

2-(Biphenyl-4-yloxy)-N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-045) (11q): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(biphenyl-4-yloxy)acetyl chloride (5e)(120 mg, 0.47 mmol) andisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (85 mg,0.39 mmol) and triethyl amine (79 mg, 0.78 mmol). The compound 11q(SO2-045) was obtained as a white solid (145 mg, 87%). M.p. 147.8-148.7°C.

HPLC 99.6% (R_(t)=14.6 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.02(dd, J=8.2, 1.4 Hz, 2H), 7.55-7.36 (m, 9H), 7.31 (t, J=7.4 Hz, 1H), 7.05(d, J=8.8 Hz, 2H [δ 7.00 minor isomer shown]), 4.87 (s, 2H [δ 4.91 minorisomer shown]), 4.73 (s, 2H), 4.48-4.42 (m, 1H), 1.33 (d, J=6.6 Hz, 6H[δ 1.17 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.55 [δ176.69 minor isomer shown], 168.58, 168.30, 157.63 [δ 157.49 minorisomer shown], 140.78, 135.04, 131.36 [δ 131.77 minor isomer shown],128.98, 128.94 [δ 129.16 minor isomer shown], 128.53, 127.71, 127.04,127.01 [δ 126.88 minor isomer shown], 115.17 [δ 115.10 minor isomershown], 68.62, 67.86 [δ 68.62 minor isomer shown], 48.98 [δ 47.02 minorisomer shown], 37.22 [δ 38.50 minor isomer shown], 21.51 [δ 20.00 minorisomer shown].

LC-MS (ESI+) m/z 428.21 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₆H₂₆N₃O₃ (M+H)⁺428.1969. found 428.1968.

SO2-046 (11r)

2-(6-Bromonaphthalen-2-yloxy)-N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-046) (11r): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(6-bromonapthalen-2-yloxy)acetyl chloride(5g) (140 mg, 0.47 mmol) andisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (85 mg,0.39 mmol) and triethyl amine (79 mg, 0.78 mmol). The compound 11r(SO2-046) was obtained as a white solid (140 mg, 75%). M.p. 97.7-98.4°C.

HPLC 98.1% (R_(t)=19.6 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ7.93-7.91 (m, 3H), 7.67 (d, J=9.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H),7.53-7.36 (m, 4H), 7.24 (dd, J=9.0, 2.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H),4.93 (s, 2H [δ 4.98 minor isomer shown]), 4.72 (s, 2H [δ 4.86 minorisomer shown]), 4.52-4.46 (m, 1H), 1.33 (d, J=6.6 Hz, 6H [δ 1.18 minorisomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.47, 168.14 [δ 168.59minor isomer shown], 156.26, 133.02, 131.36 [δ 131.80 minor isomershown], 130.63, 130.00 [δ 129.94 minor isomer shown], 129.82, 129.03 [δ129.14 minor isomer shown], 128.94, 127.63 [δ 127.68 minor isomershown], 126.75, 119.65 [δ 119.49 minor isomer shown], 117.90, 107.72,67.89 [δ 68.50 minor isomer shown], 49.03 [δ 47.10 minor isomer shown],37.23 [δ 38.65 minor isomer shown], 29.94, 21.53 [δ 19.99 minor isomershown].

LC-MS (ESI+) m/z 480.09 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₄H₂₃BrN₃O₃ (M+H)⁺480.0917. found 480.0914.

SO2-030 (11s)

2-(4-Fluorophenoxy)-N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-030) (11s): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-fluorophenoxy)acetyl chloride (5f)(100 mg, 0.53 mmol) andisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (90 mg,0.42 mmol) and triethyl amine (1.07 mg, 1.06 mmol). The compound 11s(SO2-030) was obtained as a white solid (160 mg, 82%). M.p. 83.0-85.5°C.

HPLC 99.46% (R_(t)=16.00 min, 50% CH₃CN in 0.1% TFA water 30 min); The¹H NMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.00(dd, J=8.1, 1.6 Hz, 2H [δ 8.04 minor isomer shown]), 7.56-7.41 (m, 3H),7.02-6.88 (m, 4H), 4.80 (s, 2H [δ 4.85 minor isomer shown]), 4.72 (s, 2H[δ 4.83 minor isomer shown]), 4.44-4.38 (m, 1H), 1.31 (d, J=6.7 Hz, 6H[δ 1.16 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.49 [δ177.63 minor isomer shown], 168.82 [δ 168.56 minor isomer shown], 159.17[δ 156.79 minor isomer shown], 154.25 [δ 154.23 minor isomer shown],131.44 [δ 131.86 minor isomer shown], 129.00 [δ 129.19 minor isomershown], 127.64 (d, J=272 Hz), 127.69, 126.82, 116.36 [δ 116.29 minorisomer shown], 116.11 (d, J=40.9 Hz) 116.01 [δ 115.92 minor isomershown], 68.30 [δ 68.92 minor isomer shown], 48.91 [δ 46.94 minor isomershown], 37.18 [δ 38.39 minor isomer shown], 21.46 [δ 19.97 minor isomershown]; ¹⁹F NMR (376 MHz, CDCl₃) δ −123.13.

LC-MS (ESI+) m/z 370.15 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₂₁FN₃O₃ (M+H)⁺370.1562. found 370.1567.

SO2-089 (11t)

4-(2-(Isopropyl((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethoxy)benzoicacid (SO2-089) (11t): A solution of 11aq (SO2-068) (50 mg, 0.11 mmol) intrifluoroacetic acid (3 ml) and dichloromethane (5 ml) were stirred 2 hat rt. Acetone (5 ml) was added to the reaction mixture and the solventswere evaporated under vacuo to give the pure compound 11t (SO2-089) as awhite compound. (41 mg, 95%). M.p. 211.3-213.8° C.

HPLC 100% (R_(t)=14.8 min, 40% MeOH in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, DMSO) δ 12.58(brs, 1H), 7.97-7.90 (m, 2H [δ 8.03-7.98 minor isomer shown]), 7.82 (d,J=8.8 Hz, 2H), 7.64-7.47 (m, 2H), 6.96 (d, J=8.8 Hz, 2H), 5.09 (s, 2H [δ5.02 minor isomer shown]), 4.75 (s, 2H [δ 5.00 minor isomer shown]),4.63 (s, 1H), 4.32-4.20 (m, 1H [δ 4.66-4.60 minor isomer shown]), 1.28(d, J=6.5 Hz, 6H [δ 1.07 minor isomer shown]). ¹³C NMR (100 MHz, CDCl₃)δ 176.32, 171.41, 168.58, 167.80, 162.38, 132.70 [δ 132.63 minor isomershown], 131.48 [δ 131.94 minor isomer shown], 129.22, 129.01 [δ 129.22minor isomer shown], 127.68 [δ 126.71 minor isomer shown], 122.97 [δ122.90 minor isomer shown], 114.71 [δ 114.68 minor isomer shown], 67.46[δ 67.96 minor isomer shown], 49.07 [δ 47.24 minor isomer shown], 37.24[δ 38.43 minor isomer shown], 21.46 [δ 19.96 minor isomer shown].

LC-MS (ESI+) m/z 396.15 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₂N₃O₅ (M+H)⁺396.1554. found 396.1566.

SO2-170 (11u)

2-(4-Hydroxyphenoxy)-N-isopropyl-N-((pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-170) (11u): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-hydroxyphenoxy)acetyl chloride (5s)(62 mg, 0.33 mmol) and ofN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (60mg, 0.27 mmol) and triethyl amine (55 mg, 0.54 mmol). The compound 11u(SO2-170) was isolated as a white solid. (83 mg, 83%). mp 140.0-142.4°C.

HPLC 100% (R_(t)=5.47 min, 45% MeOH in 0.1% TFA water 20 min); The ¹HNMR showed 5:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s,1H), 9.11 (s, 1H [δ 9.23 minor isomer shown]), 8.70 (dd, J=4.8, 1.4 Hz,1H [δ 8.74 minor isomer shown]), 8.30 (dt, J=8.0, 1.9 Hz, 1H), 7.43 (dd,J=7.9, 4.8 Hz, 1H), 6.88 (d, J=9.1 Hz, 2H), 6.80 (d, J=9.1 Hz, 2H), 4.78(s, 2H [δ 4.88 minor isomer shown]), 4.69 (s, 2H), 4.60-4.52 (m, 1H),1.29 (d, J=6.6 Hz, 6H [δ 1.16 minor isomer shown]); ¹³C NMR (100 MHz,CDCl₃) δ 177.39, 169.00, 166.13, 152.05, 151.05, 148.10, 135.85, 124.36,116.41 19 [δ 117.00 minor isomer shown], 115.97, 68.37, 48.88, 37.08,21.49 19 [δ 19.99 minor isomer shown].

LC-MS (ESI+) m/z 369.15 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₉H₂₁N₄O₄ (M+H)⁺369.1557. found 369.1571.

SO2-171 (11v)

2-(4-hydroxyphenoxy)-N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-171) (11v): This compound was synthesized using the same protocolsame protocol for 1 (SO1-143) except using 2-(4-hydroxyphenoxy)acetylchloride (5s) (52 mg, 0.23 mmol) andisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (52 mg,0.28 mmol) and triethyl amine (47 mg, 0.46 mmol). The compound 11v(SO2-171) was obtained as a white solid (68 mg, 80%). M.p. 155.5-158.5°C.

HPLC 100% (R_(t)=13.1 min, 40% CH₃CN in 0.1% TFA water 20 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d,J=8.2 Hz, 1H), 8.01 (dd, J=7.8, 1.7 Hz, 2H [δ 8.04 minor isomer shown]),7.54-7.43 (m, 3H), 6.85 (d, J=9.0 Hz, 2H [δ 6.80 minor isomer shown]),6.73 (d, J=9.0 Hz, 2H [δ 6.70 minor isomer shown]), 4.75 (s, 2H [δ 4.85minor isomer shown]), 4.71 (s, 2H [δ 4.80 minor isomer shown]),4.48-4.41 (m, 1H), 1.30 (d, J=6.6 Hz, 6H [δ 1.15 minor isomer shown]).¹³C NMR (101 MHz, DMSO) δ 178.76 [δ 178.92 minor isomer shown], 168.67,168.57 [δ 168.67 minor isomer shown], 168.12 [δ 168.25 minor isomershown], 152.16 [δ 152.02 minor isomer shown], 151.45, 150.38, 132.27 [δ132.45 minor isomer shown], 129.97 [δ 130.02 minor isomer shown], 127.61[δ 127.69 minor isomer shown], 126.78 [δ 126.55 minor isomer shown],116.30, 116.21 [δ 116.13 minor isomer shown], 116.16 [δ 115.91 minorisomer shown], 67.33 [δ 67.42 minor isomer shown], 48.31, 40.79, 40.58,40.37, 40.16, 39.95, 39.74, 39.53, 37.77, 21.34 [δ 19.94 minor isomershown].

LC-MS (ESI+) m/z 368.16 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₂₂N₃O₄ (M+H)⁺368.1605. found 368.1615.

SO2-075 (11w)

N-Isopropyl-N-((3-(pyridin-2-yl)-1,2,4-oxadizaol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO2-075) (11w): This compound was synthesized using the same protocolfor 11x (SO2-076) except using p-tolyloxy-acetyl chloride (5a) (42 mg,0.24 mmol) andN-((3-pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10e) (42mg, 0.20 mmol) and triethyl amine (38 mg, 0.38 mmol). The compound 11w(SO2-075) was obtained as a white compound (52 mg, 75%). M.p.125.7-126.9° C.

HPLC 96.2% (R_(t)=15.7 min, 40% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d,J=4.7 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.82 (td, J=7.8, 1.7 Hz, 1H),7.42 (dd, J=6.7, 4.9 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H [δ 7.03 minor isomershown]), 6.87 (d, J=8.5 Hz, 2H [δ 6.80 minor isomer shown]), 4.79 (s, 2H[δ 4.93 minor isomer shown]), 4.77 (s, 2H [δ 4.81 minor isomer shown]),4.49-4.38 (m, 1H), 2.29 (s, 3H [δ 2.24 minor isomer shown]), 1.29 (d,J=6.6 Hz, 6H [δ 1.16 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ177.38, 168.57 [δ 168.37 minor isomer shown], 155.96, 150.60 [δ 150.73minor isomer shown], 146.46, 137.19, 131.25, 130.30, 125.72, 123.51,114.66, 67.98 [δ 68.99 minor isomer shown], 49.01, 37.24, 21.44 [δ 19.95minor isomer shown], 20.72. LC-MS (ESI+) m/z 367.17 (M+H)⁺; HRMS(ESI+ve) m/z calculated for C₂₀H₂₃N₄O₃ (M+H)⁺367.1765. found 367.1774.

SO2-076 (11x)

N-isopropyl-N-((3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide

N-Isopropyl-N-((3-(pyridin-3-yl)-1,2,4-oxadizaol-5-yl)methyl)-2-(p-tolyloxy)acetamide11x (SO2-076): To a solution ofN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (11f) (50mg, 0.23 mmol) and triethyl amine (47 mg, 0.46 mmol) in THF (10 ml) atrt was added p-tolyloxy-acetyl chloride (5a) (51 mg, 0.27 mmol) in THF(1 ml) dropwise. As the acyl chloride was added, a precipitate wasformed and the reaction was completed in 10 min. The THF was evaporatedand the residue purified by column chromatography (EtOAc:hexane gradientelution) to obtain 11x as a white solid (69 mg, 82%). M.p. 126.5-128.3°C.

HPLC 98.3% (R_(t)=10.6 min, 35% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s,1H), 8.72 (dd, J=4.8, 1.2 Hz, 1H [δ 8.75 minor isomer shown]), 8.27 (dt,J=7.9, 1.6 Hz, 1H), 7.39 (dd, J=8.0, 4.9 Hz, 1H [δ 7.43 minor isomershown]), 7.08 (d, J=8.6 Hz, 2H [δ 7.02 minor isomer shown]), 6.86 (d,J=8.5 Hz, 2H [δ 6.77 minor isomer shown]), 4.78 (s, 2H [δ 4.88 minorisomer shown]), 4.70 (s, 2H [δ 4.78 minor isomer shown]), 4.49-4.39 (m,1H), 2.27 (s, 3H [δ 2.22 minor isomer shown]), 1.31 (d, J=6.6 Hz, 6H [δ1.16 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) ¹³C NMR (100 MHz,CDCl₃) δ 177.23, 168.60, 166.65, 155.94 [δ 155.72 minor isomer shown],152.24 [δ 152.52 minor isomer shown], 148.92 [δ 148.87 minor isomershown], 134.97, 131.30, 130.28, 123.79 [δ 123.86 minor isomer shown],123.20, 114.64 [δ 114.53 minor isomer shown], 67.91 [δ 69.02 minorisomer shown], 48.99, 48.96, 37.27 [δ 38.66 minor isomer shown], 21.52[δ 19.99 minor isomer shown], 20.72. LC-MS (ESI+) m/z 367.17 (M+H)⁺;HRMS (ESI+ve) m/z calculated for C₂₀H₂₃N₄O₃ (M+H)⁺367.1765. found367.1774.

SO2-069 (11y)

N-Isopropyl-N-((3-(pyridin-4-yl)-1,2,4-oxadizaol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO2-069) (11y): This compound was synthesized using the same protocolfor 11x (SO2-076) except using p-tolyloxy-acetyl chloride (5a) (21 mg,0.12 mmol) andN-((3-pyridin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (21 mg,0.10 mmol) (10g) and triethyl amine (19 mg, 0.19 mmol). The compound fly(SO2-069) was obtained as a white compound (27 mg, 78%). M.p.150.6-151.7° C.

HPLC 96.6% (R_(t)=14.7 min, 30% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d,J=4.8 Hz, 2H), 7.87 (d, J=4.6 Hz, 2H), 7.09 (d, J=8.1 Hz, 2H [δ 7.02minor isomer shown]), 6.87 (d, J=8.5 Hz, 2H [δ 6.76 minor isomershown]), 4.80 (s, 2H [δ 4.90 minor isomer shown]), 4.70 (s, 2H [δ 4.79minor isomer shown]), 4.51-4.40 (m, 1H), 2.29 (s, 3H [δ 2.23 minorisomer shown]), 1.32 (d, J=6.6 Hz, 6H [δ 1.16 minor isomer shown]); ¹³CNMR (100 MHz, CDCl₃) δ 177.57, 168.65, 167.05, 155.94, 150.79 [δ 150.91minor isomer shown], 134.35, 131.30, 130.29, 121.57, 114.64 [δ 114.50minor isomer shown], 67.91 [δ 69.08 minor isomer shown], 49.01, 48.97,37.27 [δ 38.61 minor isomer shown], 29.94, 21.52 [δ 19.98 minor isomershown], 20.72.

LC-MS (ESI+) m/z 367.18 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₂₃N₄O₃ (M+H)⁺367.1765. found 367.1780.

SO2-179 (11z)

N-Isopropyl-2-(60methylpyridin-3-yloxy)-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-179) (11z): A solution of 6-methylpyridin-3-ol (80 mg, 0.73 mmol),N-isopropyl-2-chloro-N-((3-phenyl-1,2,4-oxodiazol-5-yl)methyl)acetamide(19) (220 mg, 0.733 mmol) and potassium carbonate (510 mg, 3.665 mmol)in acetonitrile (25 ml) were refluxed for 14 h. The solvent wasevaporated, the residue was dissolved in ethyl acetate (20 ml) andwashed with water (2×20 ml). Solvent was dried (MgSO₄), evaporated andthe compound was purified by column chromatography (EtOAc:hexanegradient elution) to obtain a white solid (199 mg, 72%). M.p130.3-132.2° C.

HPLC 97.26% (R_(t)=8.3 min, 30% CH₃CN in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 8.27 (d, J=2.9 Hz, 1H [δ 8.26 minor isomer shown]),8.00 (dd, J=7.9, 1.6 Hz, 1H [δ 8.04 minor isomer shown]), 7.54-7.43 (m,4H), 7.20 (d, J=8.5 Hz, 1H), 4.93 (s, 2H [δ 5.01 minor isomer shown]),4.89-4.80 (m, 1H), 4.72 (s, 2H [δ 4.78 minor isomer shown]), 4.33-4.21(m, 1H [δ 4.89-4.80 minor isomer shown]), 1.35 (d, J=6.6 Hz, 6H [δ 1.16minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.25, 168.58, 166.98,153.61, 149.71, 131.50 [δ 131.94 minor isomer shown], 129.26 [δ 129.04minor isomer shown], 127.69, 126.73, 125.54, 67.68, 48.90 [δ 47.05 minorisomer shown], 47.05, 37.21, 29.93, 21.51 [δ 19.99 minor isomer shown].

LC-MS (ESI+) m/z 367.18 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₂₃N₄O₃(M+H)⁺367.1765. found 367.1759.

SO2-050 (11aa)

2-(4-Ethylphenoxy)-N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-050) (11aa): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-ethylphenoxy)acetyl chloride (5j) (90mg, 0.47 mmol) andisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (85 mg,0.39 mmol) and triethyl amine (79 mg, 0.78 mmol). The compound 11aa(SO2-050) was obtained as a white solid (120 mg, 83%). mp 106.7-109.2°C.

HPLC 95.49% (R_(t)=11.5 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 2:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.03(dd, J=7.9, 1.4 Hz, 2H), 7.55-7.38 (m, 3H), 7.11 (d, J=8.4 Hz, 2H [δ7.07 minor isomer shown]), 6.90 (d, J=8.5 Hz, 2H [δ 6.84 minor isomershown]), 4.79 (s, 2H [δ 4.86 minor isomer shown]), 4.71 (s, 2H [δ 4.83minor isomer shown]), 4.46-4.40 (m, 1H), 2.59 (q, J=7.5 Hz, 2H [δ 2.55minor isomer shown]), 1.31 (d, J=6.6 Hz, 6H [δ 1.16 minor isomershown]), 1.20 (t, J=7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 176.62 [δ176.77 minor isomer shown], 168.56 [δ 168.66 minor isomer shown], 156.14[δ 155.94 minor isomer shown], 137.73, 131.38 [δ 131.75 minor isomershown], 129.11, 128.98, 127.73 [δ 126.90 minor isomer shown], 114.72 [δ114.76 minor isomer shown], 114.65, 67.97 [δ 68.74 minor isomer shown],48.98, 37.23 [δ 38.44 minor isomer shown], 28.21, 21.48 [δ 19.99 minorisomer shown], 16.01.

LC-MS (ESI+) m/z 380.21 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₆N₃O₃ (M+H)⁺380.1969. found 380.1979.

SO2-103 (11ab)

2-(4-Ethylphenoxy)-N-isopropyl-N-((3-pyridin-3-yl)1,2,4-oxadiazol-5-yl)methylacetamide(SO2-103) (11ab): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-ethylphenoxy)acetylchloride (5j) (49mg, 0.25 mmol) and ofN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (45mg, 0.21 mmol) and triethyl amine (43 mg, 0.42 mmol). The compound 11ab(SO2-103) was isolated as a white solid. (65 mg, 81%). M.p. 104.4-106.3°C.

HPLC 95.94% (R_(t)=5.4 min, 50% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s,1H), 8.67 (brs, 1H), 8.23 (d, J=7.7 Hz, 1H), 7.42-7.29 (m, 1H), 7.04 (d,J=8.5 Hz, 2H [δ 6.98 minor isomer shown]), 6.82 (d, J=8.5 Hz, 2H [δ 6.73minor isomer shown]), 4.72 (s, 2H [δ 4.82 minor isomer shown]), 4.64 (s,2H [δ 4.74 minor isomer shown]), 4.40-4.32 (m, 1H), 2.51 (q, J=7.6 Hz,2H, [δ 2.47 minor isomer shown]), 1.25 (d, J=6.6 Hz, 6H [δ 1.16 minorisomer shown]), 1.11 (t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ177.26, 168.59, 166.65, 156.09, 152.11, 148.82, 137.79, 135.02, 129.10,114.68 [δ 114.57 minor isomer shown], 67.97 [δ 69.01 minor isomershown], 49.00, [δ 46.98 minor isomer shown], 37.29 [δ 38.61 minor isomershown], 28.19 [δ 29.93 minor isomer shown], 21.49 [δ 19.99 minor isomershown], 16.00.

LC-MS (ESI+) m/z 381.21 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₅N₄O₃(M+H)⁺381.1921. found 381.1941.

SO3-030 (11ac)

N-Isopropyl-2-phenoxy-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-030) (11ac): This compound was synthesized using the same protocolfor 11x (SO2-076) except using phenoxyacetyl chloride (5c) (55 mg, 0.32mmol) and N-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine(10f) (59 mg, 0.27 mmol) and triethyl amine (55 mg, 0.54 mmol). Thecompound 11ac (SO3-030) was obtained as a white compound (81 mg, 85%).mp 83.0-85.5° C.

HPLC 97.50% (R_(t)=11.4 min, 30% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s,1H), 8.74 (brs, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.45-7.39 (m, 1H),7.33-7.22 (m, 2H), 7.02-6.87 (m, 3H), 4.82 (s, 2H [δ 4.89 minor isomershown]), 4.71 (s, 2H [δ 4.84 minor isomer shown]), 4.51-4.37 (m, 1H),1.32 (d, J=6.6 Hz, 6H [δ 1.16 minor isomer shown]); ¹³C NMR (100 MHz,CDCl₃) δ 177.21 [δ 177.41 minor isomer shown]), 168.43, 166.62, 158.01[δ 157.83 minor isomer shown], 152.20 [δ 152.53 minor isomer shown],148.85, 134.99, 129.85, 123.83 [δ 123.19 minor isomer shown], 121.98,114.81 [δ 114.71 minor isomer shown], 67.65 [δ 68.66 minor isomershown], 48.97 [δ 47.08 minor isomer shown]), 38.62, 37.28 21.49 [δ 19.97minor isomer shown].

LC-MS (ESI+) m/z 353.16 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₁₉H₂₁N₄O₃(M+H)⁺353.1608. found 353.1614.

SO2-184 (11ad)

N-Isopropyl-2-(4-propylphenoxy)-N-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-184) (11ad): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-propylphenoxy)acetyl chloride (5k)(84 mg, 0.39 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (100 (72mg, 0.33 mmol) and triethyl amine (67 mg, 0.66 mmol). The compound 11ad(SO2-184) was obtained as a white compound (100 mg, 84%). M.p.95.1-98.0° C.

HPLC 97.74% (R_(t)=11.6 min, 50% CH₃CN in 0.1% TFA water 20 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s,1H), 8.73 (d, J=3.8 Hz, 1H), 8.29 (dt, J=8.0 Hz, J=2.0 Hz, 1H), 7.40(dd, J=8.0, 4.9 Hz, 1H), 7.09 (d, J=8.6 Hz, 2H [δ 7.03 minor isomershown]), 6.88 (d, J=8.6 Hz, 2H [δ 6.79 minor isomer shown]), 4.81 (s,1H), 4.79 (s, 2H [δ 4.89 minor isomer shown]), 4.71 (s, 2H [δ 4.79 minorisomer shown]), 4.48-4.38 (m, 1H), 2.51 (t, J=7.7 Hz, 2H [δ 2.47 minorisomer shown]), 1.63-1.52 (m, 2H), 1.32 (d, J=6.6 Hz, 6H [δ 1.16 minorisomer shown]), 0.91 (t, J=7.3 Hz, 3H [δ 0.89 minor isomer shown]); ¹³CNMR (100 MHz, CDCl₃) δ 177.38, 168.61, 166.44 [δ 166.79 minor isomershown], 156.09 [δ 155.85 minor isomer shown]), 151.55 [δ 151.20 minorisomer shown], 148.29 [δ 148.57 minor isomer shown]), 136.25 [δ 136.32minor isomer shown], 135.55 [δ 135.24 minor isomer shown], 129.70,124.09 [δ 123.57 minor isomer shown], 114.58, 114.48, 67.86 [δ 69.00minor isomer shown], 49.01 [δ 47.02 minor isomer shown], 37.35 [δ 38.66minor isomer shown], 29.94, 24.93, 21.52 [δ 19.99 minor isomer shown],14.02.

LC-MS (ESI+) m/z 395.21 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₇N₄O₃ (M+H)⁺395.2078. found 395.2080.

SO3-026 (11ae)

2-(4-Butylphenoxy)-N-isopropyl-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-026) (11ae): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-butylphenoxy)acetyl chloride (5l)(76 mg, 0.36 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (100 (61mg, 0.28 mmol) and triethyl amine (57 mg, 0.56 mmol). The compound 11ae(SO3-026) was obtained as a white compound (94 mg, 82%). M.p. 94.5-95.2°C.

HPLC 97.51% (R_(t)=10.2 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.29 (s,1H [δ 9.26 minor isomer shown]), 8.80-8.73 (m, 1H), 8.44 (d, J=7.5 Hz,1H [δ 8.33 minor isomer shown]), 7.56-7.52 (m, 1H [δ 7.50 minor isomershown]), 7.09 (d, J=8.6 Hz, 2H [δ 7.02 minor isomer shown]), 6.87 (d,J=8.6 Hz, 2H [δ 6.78 minor isomer shown]), 4.78 (s, 2H [δ 4.90 minorisomer shown]), 4.70 (s, 2H [δ 4.80 minor isomer shown]), 4.47-4.40 (m,1H), 2.54 (t, J=7.3 Hz, 2H [δ 2.48 minor isomer shown]), 1.59-1.46 (m,2H), 1.36-1.29 (m, 2H), 1.32 (d, J=6.6 Hz, 6H [δ 1.16 minor isomershown]), 0.91 (t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 177.23,168.58, 166.66, 156.07, 152.24 [δ 152.54 minor isomer shown]), 148.93,136.46, 134.97, 129.64, 123.80, 123.21, 114.59 [δ 114.50 minor isomershown]), 67.91, 48.97, 37.29, 34.95, 34.03, 22.53, 21.50 [δ 19.99 minorisomer shown], 14.20.

LC-MS (ESI+) m/z 409.23 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₃H₂₉N₄O₃(M+H)⁺409.2234. found 409.2238.

SO3-050 (11af)

N-Isopropyl-2-(4-pentylphenoxy)-N-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-050) (11af): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-pentylphenoxy)acetyl chloride (5m)(77 mg, 0.32 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (59mg, 0.27 mmol) and triethyl amine (55 mg, 0.54 mmol). The compound 11af(SO3-050) was obtained as a white compound (95 mg, 83%). M.p. 93.0-95.9°C.

HPLC 96.51% (R_(t)=17.1 min, 70% MeOH in 0.1% TFA water 20 min); ¹H NMR(400 MHz, CDCl₃) δ 9.19 (s, 1H [δ 9.24 minor isomer shown]), 8.67 (dd,J=4.9, 1.6 Hz, 1H), 8.28-8.19 (m, 1H), 7.43-7.28 (m, 1H), 7.02 (d, J=8.4Hz, 2H [δ 6.95 minor isomer shown]), 6.81 (d, J=8.5 Hz, 2H [δ 6.72 minorisomer shown]), 4.72 (s, 2H [δ 4.83 minor isomer shown]), 4.64 (s, 2H [δ4.74 minor isomer shown]), 4.41-4.32 (m, 1H), 2.46 (t, J=7.8 Hz, 2H [δ2.41 minor isomer shown]), 1.55-1.39 (m, 2H), 1.33-1.05 (m, 4H), 1.25(d, J=6.7 Hz, 6H [δ 1.09 minor isomer shown]), 0.81 (t, J=6.6 Hz, 3H);¹³C NMR (100 MHz, CDCl₃) δ 177.29 [δ 177.50 minor isomer shown], 168.62,166.79, 166.56 [δ 166.79 minor isomer shown], 156.07 [δ 155.82 minorisomer shown], 152.19, 151.88 [δ 152.19 minor isomer shown], 148.60,136.51 [δ 136.33 minor isomer shown], 135.25, 129.63 [δ 129.59 minorisomer shown], 123.97, 114.60 [δ 114.50 minor isomer shown], 67.90 [δ69.04 minor isomer shown], 49.00 [δ 47.08 minor isomer shown], 37.30 [δ38.65 minor isomer shown], 35.24, 31.69, 31.57 [δ 29.93 minor isomershown], 22.77, 21.51 [δ 19.99 minor isomer shown], 14.29.

LC-MS (ESI+) m/z 423.24 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₄H₃₁N₄O₃(M+H)⁺423.2391. found 423.2393.

SO3-051 (11ag)

2-(4-Hexylphenoxy)-N-isopropyl-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-051) (11ag): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-hexylphenoxy)acetyl chloride (5n)(97 mg, 0.38 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (100 (69mg, 0.32 mmol) and triethyl amine (65 mg, 0.64 mmol). The compound 11ag(SO3-051) was obtained as a white compound (120 mg, 87%). M.p.94.4-96.1° C.

HPLC 93.76% (R_(t)=7.7 min, 80% MeOH in 0.1% TFA water 20 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.28 (s,1H), 8.75 (brs, 1H), 8.33 (d, J=7.9 Hz, 1H), 7.50-7.40 (m, 1H), 7.09 (d,J=8.6 Hz, 2H [δ 7.03 minor isomer shown]), 7.87 (d, J=8.7 Hz, 2H [δ 6.79minor isomer shown]), 4.79 (s, 2H [δ 4.90 minor isomer shown]), 4.71 (s,2H [δ 4.81 minor isomer shown]), 4.49-4.36 (m, 1H), 2.53 (t, J=7.8 Hz,2H), 1.60-1.48 (m, 2H), 1.35-1.22 (m, 6H), 1.32 (d, J=6.6 Hz, 6H [δ 1.16minor isomer shown]), 0.91-0.83 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ177.34, 168.59, 166.52, 156.06, 151.72 [δ 152.30 minor isomer shown],148.48 [δ 148.68 minor isomer shown], 136.52, 135.38, 129.63 [δ 129.59minor isomer shown], 114.60, 114.50, 67.91 [δ 69.02 minor isomer shown],48.99, 37.31 [δ 38.64 minor isomer shown], 35.28, 31.96, 31.86, 29.18,22.85, 21.52 [δ 19.99 minor isomer shown], 14.35.

LC-MS (ESI+) m/z 437.24 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₅H₃₃N₄O₃(M+H)⁺437.2547. found 437.2548.

SO3-066 (11ah)

N-Isopropyl-2-(4-cyclohexylphenoxy)-N-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-066) (11ah): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-cyclohexylphenoxy)acetyl chloride(5o) (79 mg, 0.31 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (57mg, 0.26 mmol) and triethyl amine (53 mg, 0.52 mmol). The compound 11ah(SO3-054) was obtained as a sticky solid (88 mg, 78%).

HPLC 97.00% (R_(t)=17.0 min, 70% MeOH in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.74 (d, J=3.8 Hz, 1H), 8.30 (d, J=8.0Hz, 1H), 7.48-7.36 (m, 1H), 7.12 (d, J=8.7 Hz, 2H [δ 7.06 minor isomershown]), 6.88 (d, J=8.7 Hz, 2H [δ 6.80 minor isomer shown]), 4.78 (s, 2H[δ 4.89 minor isomer shown]), 4.71 (s, 2H [δ 4.81 minor isomer shown]),4.46-4.39 (m, 1H), 2.48-2.37 (m, 1H), 1.87-1.67 (m, 6H), 1.42-1.28 (m,4H), 1.32 (d, J=6.6 Hz, 6H [δ 1.17 minor isomer shown]); ¹³C NMR (100MHz, CDCl₃) δ 177.26 [δ 177.47 minor isomer shown], 168.57, 166.88,166.66 [δ 166.88 minor isomer shown], 156.11 [δ 155.86 minor isomershown], 152.20 [δ 152.49 minor isomer shown], 148.91 [δ 148.86 minorisomer shown], 141.82, 141.75, 134.96, 128.03, 123.86, 114.60 [δ 114.50minor isomer shown], 67.88 [δ 69.03 minor isomer shown], 48.98 [δ 47.07minor isomer shown], 43.88, 37.30 [δ 38.66 minor isomer shown], 34.85,27.13 [δ 29.93 minor isomer shown], 26.36, 21.51 [δ 19.99 minor isomershown].

LC-MS (ESI+) m/z 435.24 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₅H₃₁N₄O₃(M+H)⁺435.2391. found 435.2395.

SO3-080 (11ai)

N-Isopropyl-2-(4-isopropylphenoxy)-N-((3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-080) (11ai): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-isopropylphenoxy)acetyl chloride(5p) (62 mg, 0.29 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (53mg, 0.24 mmol) and triethyl amine (49 mg, 0.48 mmol). The compound 11ai(SO3-080) was obtained as a sticky solid (77 mg, 81%).

HPLC 99.09% (R_(t)=6.7 min, 50% CH₃CN in 0.1% TFA water 20 min); ¹H NMR(400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.73 (d, J=4.1 Hz, 1H), 8.30 (dt,J=8.0, 1.8 Hz, 1H), 7.40 (dd, J=7.7, 5.0 Hz, 1H), 7.14 (d, J=8.6 Hz, 2H[δ 7.08 minor isomer shown]), 6.89 (d, J=8.7 Hz, 2H [δ 6.81 minor isomershown]), 4.79 (s, 2H [δ 4.89 minor isomer shown]), 4.71 (s, 2H [δ 4.81minor isomer shown]), 4.47-4.39 (m, 1H), 2.90-2.76 (m, 1H), 1.32 (d,J=6.6 Hz, 6H [δ 1.17 minor isomer shown]), 1.20 (d, J=6.9 Hz, 6H); ¹³CNMR (100 MHz, CDCl₃) δ 177.26 [δ 177.47 minor isomer shown], 168.56,166.65 [δ 166.88 minor isomer shown], 156.11 [δ 155.88 minor isomershown], 152.22 [δ 152.52 minor isomer shown], 148.91, 142.44, 134.96,127.66, 123.81 [δ 123.25 minor isomer shown], 114.64 [δ 114.53 minorisomer shown], 67.89 [δ 69.01 minor isomer shown], 48.98 [δ 47.06 minorisomer shown], 38.65, 37.30, 33.49, 29.93, 24.37, 21.50 [δ 19.99 minorisomer shown].

LC-MS (ESI+) m/z 395.22 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₇N₄O₃(M+H)⁺395.2078. found 395.2074.

SO3-079 (11aj)

N-Isopropyl-2-(4-tert-butylphenoxy)-N-((3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-079) (11aj): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-tert-butylphenoxy)acetyl chloride(5r) (62 mg, 0.27 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (50mg, 0.23 mmol) and triethyl amine (47 mg, 0.46 mmol). The compound 11aj(SO3-079) was obtained as a sticky colorless solid (78 mg, 83%).

HPLC 97.96% (R_(t)=9.1 min, 50% CH₃CN in 0.1% TFA water 20 min); ¹H NMR(400 MHz, CDCl₃) δ 9.28 (s, 1H), 8.73 (brs, 1H), 8.31 (d, J=8.0 Hz, 1H),7.40 (dd, J=7.7, 4.9 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H [δ 7.24 minor isomershown]), 6.89 (d, J=8.7 Hz, 2H [δ 6.81 minor isomer shown]), 4.79 (s, 2H[δ 4.89 minor isomer shown]), 4.71 (s, 2H [δ 4.83 minor isomer shown]),4.43-4.33 (m, 1H), 1.32 (d, J=6.6 Hz, 6H [δ 1.16 minor isomer shown]),1.27 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 177.27 [δ 177.48 minor isomershown], 168.62, 168.53, 166.64 [δ 166.86 minor isomer shown], 155.76 [δ155.53 minor isomer shown], 152.23 [δ 152.52 minor isomer shown],148.89, 144.69, 134.97, 126.64 [δ 126.60 minor isomer shown], 123.87 [δ123.26 minor isomer shown], 114.26 [δ 114.15 minor isomer shown], 67.75[δ 68.86 minor isomer shown], 48.98 [δ 47.00 minor isomer shown], 38.62,37.32 [δ 38.62 minor isomer shown], 34.35, 31.70 [δ 31.67 minor isomershown], 31.67, 29.94, 21.52 [δ 20.01 minor isomer shown].

LC-MS (ESI+) m/z 409.21 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₃H₂₉N₄O₃(M+H)⁺409.2234. found 409.2233.

SO3-089 (11ak)

N-Isopropyl-2-(4-isobutylphenoxy)-N-((3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-089) (11ak): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-isobutylphenoxy)acetyl chloride (5q)(74 mg, 0.33 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (60mg, 0.27 mmol) and triethyl amine (55 mg, 0.54 mmol). The compound 11ak(SO3-089) was obtained as a white solid (97 mg, 88%). M.p. 121.5-123.7°C.

HPLC 98.31% (R_(t)=10.8 min, 50% CH₃CN in 0.1% TFA water 20 min); ¹H NMR(400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.74 (brs, 1H), 8.29 (d, J=7.8 Hz, 1H),7.45-7.39 (m, 1H), 7.05 (d, J=8.3 Hz, 2H [δ 7.00 minor isomer shown]),6.87 (d, J=8.6 Hz, 2H [δ 6.79 minor isomer shown]), 4.79 (s, 2H [δ 4.90minor isomer shown]), 4.71 (s, 2H [δ 4.81 minor isomer shown]),4.50-4.40 (m, 1H), 2.40 (d, J=7.2 Hz, 2H [δ 2.36 minor isomer shown]),2.36 (d, J=7.1 Hz, 1H), 1.86-1.70 (m, 1H), 1.32 (d, J=6.6 Hz, 6H [δ 1.16minor isomer shown]), 0.87 (d, J=6.6 Hz, 6H [δ 0.85 minor isomershown]); ¹³C NMR (100 MHz, CDCl₃) δ 177.24, 168.59 [δ 166.72 minorisomer shown], 166.72, 156.15, 155.89, 152.14, 148.89, 135.26, 134.93,130.35, 67.93 [δ 69.06 minor isomer shown], 48.98 [δ 47.06 minor isomershown], 44.73, 37.30 [δ 38.65 minor isomer shown], 30.53 [δ 29.93 minorisomer shown], 22.52, 21.51 [δ 19.98 minor isomer shown].

LC-MS (ESI+) m/z 409.23 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₃H₂₉N₄O₃(M+H)⁺409.2234. found 409.2231.

SO3-074 (11al)

N-Isopropyl-2-(4-propylphenoxy)-N-((3-(pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-074) (11al): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-propylphenoxy)acetyl chloride (5k)(47 mg, 0.22 mmol) andN-((3-pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10h)(40 mg, 0.18 mmol) and triethyl amine (37 mg, 0.26 mmol). The compound11al (SO3-074) was obtained as a white solid (58 mg, 81%). M.p.92.7-94.0° C.

HPLC 97.18% (R_(t)=12.1 min, 50% CH₃CN in 0.1% TFA water 20 min); ¹H NMR(400 MHz, CDCl₃) δ 9.41-9.26 (m, 3H), 7.09 (d, J=8.5 Hz, 2H [δ 7.01minor isomer shown]), 6.87 (d, J=8.6 Hz, 2H [δ 6.75 minor isomershown]), 4.79 (s, 2H [δ 4.92 minor isomer shown]), 4.71 (s, 2H),4.49-4.41 (m, 1H), 2.52 (t, J=7.6 Hz, 2H [δ 2.45 minor isomer shown]),1.64-1.47 (m, 2H), 1.32 (d, J=6.8 Hz, 6H [δ 1.17 minor isomer shown]),0.91 (t, J=7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 177.87, 168.67,164.52, 160.62 [δ 160.82 minor isomer shown], 155.72 [δ 156.04 minorisomer shown], 136.33, 129.71, 121.78, 114.54 [δ 114.40 minor isomershown], 67.83, 49.03, 49.00, 37.34 [δ 38.87 minor isomer shown], 24.92,21.53 [δ 20.05 minor isomer shown], 14.02.

LC-MS (ESI+) m/z 396.20 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₆N₅O₃(M+H)⁺396.2030. found 396.2031.

SO3-057 (11am)

N-Isopropyl-2-(4-propylphenoxy)-N-((3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-057) (11am): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-propylphenoxy)acetyl chloride (80mg, 0.38 mmol) andN-((3-pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10j) (69mg, 0.30 mmol) and triethyl amine (61 mg, 0.60 mmol). The compound 11am(SO3-057) was obtained as a sticky solid (100 mg, 85%).

HPLC 97.25% (R_(t)=11.1 min, 50% MeOH in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 9.29 (d, J=1.4 Hz, 1H [δ 9.26 minor isomer shown]),8.75-8.67 (m, 2H), 7.08 (d, J=8.6 Hz, 2H [δ 7.01 minor isomer shown]),6.86 (d, J=8.6 Hz, 2H [δ 6.77 minor isomer shown]), 6.77 (d, J=8.5 Hz,1H), 4.78 (s, 2H [δ 4.94 minor isomer shown]), 4.76 (s, 1H [δ 4.79 minorisomer shown]), 4.49-4.33 (m, 1H), 2.50 (t, J=7.8 Hz, 2H [δ 2.45 minorisomer shown]), 1.63-1.49 (m, 2H), 1.30 (d, J=6.6 Hz, 6H [δ 1.15 minorisomer shown]), 0.90 (t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ178.00, 168.64, 166.65 [δ 166.86 minor isomer shown], 156.08 [δ 155.82minor isomer shown], 146.96, [δ 146.67 minor isomer shown], 145.02 [δ145.09 minor isomer shown], 144.62, 142.47, 136.29, 129.72 [δ 129.67minor isomer shown], 114.58 [δ 114.50 minor isomer shown], 67.92 [δ69.16 minor isomer shown], 49.02 [δ 47.08 minor isomer shown], 37.35 [δ38.85 minor isomer shown], 29.93, 24.92, 21.49 [δ 19.96 minor isomershown], 14.02.

LC-MS (ESI+) m/z 396.19 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₆N₅O₃(M+H)⁺396.2030. found 396.2028.

SO3-054 (11an)

2(-4-Butylphenoxy)-N-isopropyl-N-((3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methylecetamide(SO3-054) (11an): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-butylphenoxy)acetyl chloride (5l)(50 mg, 0.24 mmol) andN-((3-pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10j) (43mg, 0.20 mmol) and triethyl amine (41 mg, 0.40 mmol). The compound 11an(SO3-054) was obtained as a greenish sticky solid (64 mg, 78%).

HPLC 97.97% (R_(t)=9.7 min, 70% MeOH in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 9.30 (d, J=1.4 Hz, 1H), 9.27 (s, 1H), 8.77-8.66 (m,1H), 7.09 (d, J=8.6 Hz, 2H, [δ 7.02 minor isomer shown]), 6.87 (d, J=8.6Hz, 2H, [δ 6.78 minor isomer shown]), 4.80 (s, 2H, [δ 4.95 minor isomershown]), 4.76 (s, 2H, [δ 4.80 minor isomer shown]), 4.48-4.37 (m, 1H),2.53 (t, J=7.7 Hz, 2H), 1.58-1.48 (m, 2H), 1.37-1.26 (m, 2H), 1.30 (d,J=6.7 Hz, 6H, [δ 1.16 minor isomer shown]), 0.90 (t, J=7.3 Hz, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 178.00, 168.64, 166.64, 156.05 [δ 155.78 minorisomer shown], 146.65 [δ 146.94 minor isomer shown], 145.00 [δ 145.08minor isomer shown], 144.61, 142.47 [δ 142.08 minor isomer shown],136.49 [δ 136.57 minor isomer shown], 129.65 [δ 129.80 minor isomershown], 114.60 [δ 114.53 minor isomer shown], 67.93 [δ 69.17 minorisomer shown], 49.01 [δ 47.13 minor isomer shown], 37.34 [δ 38.85 minorisomer shown], 34.94, 34.00, 31.15, 29.92, 22.52 [δ 21.11 minor isomershown], 21.47 [δ 19.95 minor isomer shown], 14.17.

LC-MS (ESI+) m/z 410.222 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₈N₅O₃(M+H)⁺410.2187. found 410.2185.

SO3-096 (11ao)

N-Isopropyl-2-(4-propylphenoxy)-N-((3-(pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-096) (11ao): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-propylhenoxy)acetyl chloride (5k)(47 mg, 0.22 mmol) andN-((3-pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10i)(40 mg, 0.18 mmol) and triethyl amine (37 mg, 0.36 mmol). The compoundSO3-096 11ao was obtained as a colorless sticky solid (97 mg, 88%).

HPLC 97.92% (R_(t)=7.1 min, 50% CH₃CN in 0.1% TFA water 20 min); ¹H NMR(400 MHz, CDCl₃) δ 8.96 (d, J=4.9 Hz, 2H), 7.45 (t, J=4.9 Hz, 1H, [δ7.48 minor isomer shown]), 7.10 (d, J=8.6 Hz, 2H [δ 7.04 minor isomershown]), 6.88 (d, J=8.7 Hz, 2H [δ 6.81 minor isomer shown]), 4.83 (s, 2H[δ 4.99 minor isomer shown]), 4.80 (s, 2H [δ 4.81 minor isomer shown]),4.50-4.25 (m, 1H) 2.52 (t, J=7.7 Hz, 2H [δ 2.48 minor isomer shown]),1.66-1.51 (m, 2H [δ 1.46-1.38 minor isomer shown]), 1.28 (d, J=6.6 Hz,2H [δ 1.14 minor isomer shown]), 0.92 (t, J=7.3 Hz, 3H); ¹³C NMR (100MHz, CDCl₃) δ 168.62 [δ 167.85 minor isomer shown], 158.19, 156.27,156.09, 136.24, 129.73, 122.37, 114.59, 67.97 [δ 69.02 minor isomershown], 49.02 [δ 47.00 minor isomer shown], 37.36 [δ 38.85 minor isomershown], 37.34, 24.93 [δ 29.93 minor isomer shown], 21.42 [δ 19.90 minorisomer shown], 14.02.

LC-MS (ESI+) m/z 396.19 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₆N₅O₃(M+H)⁺396.2030. found 396.2025.

SO3-126 (11ap)

N-Isopropyl-2-(4-propylphenoxy)-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO3-126) (11ap): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 2-(4-propylphenoxy)acetyl chloride (5k)(130 mg, 0.61 mmol) andN-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10a) (128 mg,0.55 mmol) and triethyl amine (112.3 mg, 11.10 mmol). The compound 11ap(SO3-126) was obtained as a white (195 mg, 87%). mp 121.7-122.3° C.

HPLC 99.33% (R_(t)=11.1 min, 45% MeOH in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 7.90 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 2H), 7.07 (d,J=8.6 Hz, 2H [δ 7.03 minor isomer shown]), 6.87 (d, J=8.6 Hz, 2H [δ 6.82minor isomer shown]), 4.77 (s, 2H [δ 4.83 minor isomer shown]), 4.69 (s,2H [δ 4.82 minor isomer shown]), 4.45-4.34 (m, 1H), 2.54-2.46 (m, 2H),2.40 (d, J=3.8 Hz, 3H [δ 2.39 minor isomer shown]), 1.62-1.53 (m, 2H),1.29 (d, J=6.6 Hz, 6H [δ 1.13 minor isomer shown]), 0.91 (t, J=7.3 Hz,3H); ¹³C NMR (100 MHz, CDCl₃) δ 176.43 [δ 176.57 minor isomer shown]),168.50 [δ 168.56 minor isomer shown]), 156.18 [δ 155.99 minor isomershown]), 141.66 [δ 142.14 minor isomer shown]), 136.16, 129.69 [δ 129.83minor isomer shown]), 127.65, 124.09 [δ 123.58 minor isomer shown]),114.64 [δ 114.59 minor isomer shown]), 67.99 [δ 68.74 minor isomershown]), 48.94 [δ 46.89 minor isomer shown]), 37.37 [δ 38.41 minorisomer shown]), 37.22, 24.92, 21.82, 21.47 [δ 19.98 minor isomershown]), 14.03.

LC-MS (ESI+) m/z 408.24 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₄H₃₀N₃O₃(M+H)⁺408.2282. found 409.2279.

SO2-068 11aq

tert-Butyl4-(2-(isopropyl((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethoxy)benzoate(SO2-068) (11aq): A solution of tert-Butyl 4-hydroxybenzoate (28) (26mg, 0.14 mmol),N-isopropyl-2-chloro-N-((3-phenyl-1,2,4-oxodiazol-5-yl)methyl)acetamide(19) (40 mg, 0.14 mmol) and potassium carbonate (97 mg, 0.7 mmol) inacetonitrile (20 ml) were refluxed overnight. Acetonitile was evaporatedand the residue was dissolved in ethyl acetate (20 ml) and washed withwater (20 ml×2). Organic solvent was dried (MgSO₄) and the product waspurified by column chromatography (EtOAc:hexane gradient elution) toobtain 11aq as a white solid (50 mg, 80%). M.p. 143.0-144.4° C.

HPLC 99.7% (R_(t)=14.1 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d,J=8.8 Hz, 2H [δ 8.01 minor isomer shown]), 7.92 (d, J=8.8 Hz, 2H [δ 7.88minor isomer shown]), 7.50-7.38 (m, 3H), 6.96 (d, J=8.9 Hz, 2H [δ 6.93minor isomer shown]), 4.86 (s, 2H [δ 4.91 minor isomer shown]), 4.69 (s,2H [δ 4.78 minor isomer shown]), 4.41-4.31 (m, 1H), 1.55 (s, 9H), 1.29(d, J=6.6 Hz, 6H [δ 1.14 minor isomer shown]). ¹³C NMR (100 MHz, CDCl₃)δ 176.37 [δ 176.47 minor isomer shown], 168.57, 167.84 [δ 167.93 minorisomer shown], 165.83, 165.64, 161.35, 159.73, 131.87, 131.75 [δ 131.68minor isomer shown], 131.43, 129.00 [δ 129.19 minor isomer shown],127.69, 126.75, 125.77, 124.71, 115.17, 114.35 [δ 114.30 minor isomershown], 80.98 [δ 80.81 minor isomer shown], 77.56, 77.44, 77.35, 77.24,77.03, 76.92, 76.71, 67.56 [δ 68.11 minor isomer shown], 49.02 (47.15),37.22 [δ 38.41 minor isomer shown], 28.48 [δ 29.93 minor isomer shown],28.46, 21.48 [δ 19.98 minor isomer shown].

LC-MS (ESI+) m/z 469.26 (M+NH₄)⁺; HRMS (ESI+ve) m/z calculated forC₂₅H₃₀N₃O₅ (M+H)⁺452.2180. found 452.2191.

SO1-157 (12a)

N-Isobutyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO1-157) (12a): This compound was synthesized using the same protocolfor 1 (SO1-143) except using p-tolyloxy-acetyl chloride (5a) (160 mg,0.87 mmol) and isobutyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine(10m) (110 mg, 0.43 mmol) and triethyl amine (88 mg, 0.87 mmol). Thecompound 12a (SO1-157) was isolated as a white solid (130 mg, 87%). M.p.78.4-79.8° C.

HPLC 99.27% (R_(t)=11.8 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 1.5:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.92(d, J=8.2 Hz, 2H), 7.30-7.25 (m, 2H), 7.08 (d, J=8.3 Hz, 2H [δ 7.04minor isomer shown]), 6.86 (d, J=8.6 Hz, 2H [δ 6.81 minor isomershown]), 4.85 (s, 2H [δ 4.93 minor isomer shown]), 4.79 (s, 2H [δ 4.86minor isomer shown]), 3.36 (d, J=7.7 Hz, 2H [δ 3.34 minor isomershown]), 2.41 (s, 3H [δ 2.42 minor isomer shown]), 2.27 (s, 3H [δ 2.24minor isomer shown]), 2.06-1.94 (m, 1H), 1.01 (d, J=6.6 Hz, 6H [δ 0.86minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 175.43 [δ 175.48 minorisomer shown], 169.22 [δ 169.08 minor isomer shown], 168.61 [δ 168.79minor isomer shown], 156.04 [δ 155.63 minor isomer shown], 141.82 [δ142.15 minor isomer shown], 131.21 [δ 131.33 minor isomer shown],130.24, 129.74 [δ 129.84 minor isomer shown], 127.66 [δ 127.67 minorisomer shown], 123.92 [δ 123.53 minor isomer shown], 114.82 [δ 114.54minor isomer shown], 67.23 [δ 68.55 minor isomer shown], 55.50 [δ 54.51minor isomer shown], 42.10 [δ 43.59 minor isomer shown], 27.73 [δ 26.86minor isomer shown], 21.85, [δ 20.75 minor isomer shown], 20.28 [δ 20.15minor isomer shown].

LC-MS (ESI+) m/z 394.20 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₃H₂₈N₃O₃ (M+H)⁺394.2125. found 394.2127.

SO2-012 (12b)

N-Ethyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO2-012) (12b): This compound was synthesized using the same protocolfor 1 (SO1-143) except using p-tolyloxy-acetyl chloride (5a) (54 mg,0.28 mmol) and ethyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (10l)(50 mg, 0.23 mmol) and triethyl amine (47 mg, 0.46 mmol). The compound12b (SO2-012) was obtained as a white solid (70 mg, 82%). M.p.83.4-84.0° C.

HPLC 99.6% (R_(t)=9.0 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 2:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d,J=8.1 Hz, 2H [δ 7.91 minor isomer shown]), 7.27 (d, J=8.7 Hz, 2H [δ 7.29minor isomer shown]), 7.10 (d, J=8.2 Hz, 2H [δ 7.03 minor isomershown]), 6.87 (d, J=8.6 Hz, 2H [δ 6.79 minor isomer shown]), 4.84 (s, 2H[δ 4.91 minor isomer shown]), 4.78 (s, 2H [δ 4.82 minor isomer shown]),3.63 (q, J=7.1 Hz, 2H [δ 3.59 minor isomer shown]), 2.41 (s, 3H [δ 2.42minor isomer shown]), 2.29 (s, 3H [δ 2.24 minor isomer shown]), 1.29 (t,J=7.1 Hz, 3H [δ 1.16 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ175.56 [δ 175.49 minor isomer shown], 168.86 [δ 168.80 minor isomershown], 168.66 [δ 168.48 minor isomer shown], 156.00 [δ 155.65 minorisomer shown], 141.85 [δ 142.12 minor isomer shown], 131.27 [δ 131.32minor isomer shown], 130.30 [δ 130.27 minor isomer shown], 130.25 129.75[δ 129.82 minor isomer shown], 127.66, 123.89 [δ 123.56 minor isomershown], 114.72 [δ 114.52 minor isomer shown], 67.61 [δ 68.52 minorisomer shown], 43.31 [δ 42.97 minor isomer shown], 41.30 [δ 42.72 minorisomer shown], 21.83, 20.74 [δ 20.68 minor isomer shown], 14.14 [δ 12.56minor isomer shown].

LC-MS (ESI+) m/z 366.19 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₄N₃O₃ (M+H)⁺366.1812. found 366.1810.

SO1-184 (12c)

N-Methyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO1-184) (12c): This compound was synthesized using the same protocolfor SO1-143 1 except using p-tolyloxy-acetyl chloride (5a) (81 mg, 0.44mmol) and methyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine (10k) (60mg, 0.30 mmol) and triethyl amine (60 mg, 0.59 mmol). The compound 12c(SO1-184) was obtained as a white solid (100 mg, 95%). M.p. 99.1-100.9°C.

HPLC 96% (R_(t)=7.4 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹H NMRshowed 2:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d,J=8.3 Hz, 2H [δ 7.90 minor isomer shown]), 7.30-7.26 (d, J=7.9 Hz, 2H),7.14-7.07 (d, J=8.1 Hz, 2H [δ 7.03 minor isomer shown]), 6.87 (d, J=8.6Hz, 2H [δ 6.78 minor isomer shown]), 4.88 (s, 2H [δ 4.94 minor isomershown]), 4.78 (s, 2H [δ 4.82 minor isomer shown]), 3.28 (s, 3H [δ 3.12minor isomer shown]), 2.42 (s, 3H), 2.28 (s, 3H [δ 2.23 minor isomershown]); ¹³C NMR (100 MHz, CDCl₃) δ 175.13 [δ 175.03 minor isomershown], 169.08 [δ 168.92 minor isomer shown], 168.80 [δ 168.68 minorisomer shown], 155.58 [δ 155.89 minor isomer shown], 141.91 [δ 142.12minor isomer shown], 131.32 [δ 131.38 minor isomer shown], 130.29,129.82, 129.77, 127.65, 123.82 [δ 123.54 minor isomer shown], 114.76, [δ114.44 minor isomer shown], 67.57 [δ 68.37 minor isomer shown], 67.53 [δ67.49 minor isomer shown], 43.98 [δ 45.45 minor isomer shown], 35.78,35.76, 35.22, 21.85 [δ 21.83 minor isomer shown], 20.75 [δ 20.74 minorisomer shown].

LC-MS (ESI+) m/z 352.17 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₂N₃O₃ (M+H)⁺352.1656. found 352.1678.

SO2-007 (12d)

N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO2-007) (12d): This compound was synthesized using the same protocolfor 1 (SO1-143) except using

p-tolyloxy-acetyl chloride (5a) (60 mg, 0.32 mmol) andC-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)-methylamine (10n) (50 mg, 0.26 mmol)and triethyl amine (50 mg, 0.53 mmol). The compound 12d (SO2-007) wasobtained as a white solid (70 mg, 79%). M.p. 113.7-115.5° C.

HPLC 99.9% (R_(t)=6.5 min, 60% CH₃CN in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 7.94 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 7.13(d, J=8.2 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 4.84 (d, J=5.9 Hz, 2H), 4.59(s, 2H), 2.42 (s, 3H), 2.31 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 175.46,169.14, 168.66, 155.20, 142.02, 131.98, 130.49, 129.82, 127.64, 123.67,114.82, 67.74, 67.70, 67.66, 35.46, 21.85, 20.77.

LC-MS (ESI+) m/z 360.14 (M+Na)⁺; HRMS (ESI+ve) m/z calculated forC₁₉H₂₀N₃O₃ (M+H)⁺338.1499. found 338.1505.

SO2-070 (12e)

N-Tert-butyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl-2-(p-tolyloxy)acetamide(SO2-070) (12e): This compound was synthesized using the same protocolfor 1 (SO1-143) except using p-tolyloxy-acetyl chloride (5a) (76 mg,0.41 mmol) and tert-butyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine(10o) (45 mg, 0.18 mmol) and triethyl amine (36 mg, 0.22 mmol). Thecompound 12e (SO2-070) was obtained as a white compound (53 mg, 75%). mp150.6-151.7° C.

HPLC 97.7% (R_(t)=18.3 min, 60% CH₃CN in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 7.92 (d, J=8.2 Hz, 2H), 7.32-7.27 (m, 2H), 7.07-6.99(m, 2H), 6.79 (d, J=8.6 Hz, 2H), 4.95 (s, 2H), 4.76 (s, 2H), 2.42 (s,3H), 2.24 (s, 3H), 1.47 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 176.97,169.45, 168.78, 155.88, 142.11, 131.07, 130.17, 129.81, 127.66, 123.62,114.55, 77.58, 77.26, 76.94, 69.89, 69.81, 59.15, 40.71, 40.64, 29.94,28.47, 21.88, 21.83, 20.72, 20.68.

LC-MS (ESI+) m/z 294.21 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₃H₂₈N₃O₃ (M+H)⁺394.2125. found 394.2120.

SO3-084 (12f)

N-Cyclopropyl-N-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)acetamide(SO3-084) (12f): This compound was synthesized using the same protocolfor 1 (SO1-143) except using p-tolyloxy-acetyl chloride (5a) (72 mg,0.39 mmol) and cyclopropyl-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-amine(10p) (75 mg, 0.33 mmol) and triethyl amine (67 mg, 0.66 mmol). Thecompound 12f (SO3-084) was isolated as a white solid (116 mg, 79%). M.p.113.8-115.2° C.

HPLC 94.78% (R_(t)=6.2 min, 70% MeOH in 0.1% TFA water 20 min); ¹H NMR(400 MHz, CDCl₃) δ 7.93 (d, J=8.0 Hz, 2H), 7.31-7.23 (m, 2H), 7.06 (d,J=8.2 Hz, 2H), 6.86 (d, J=8.3 Hz, 2H), 4.97 (s, 2H), 4.88 (s, 2H),3.10-3.02 (m, 1H), 2.42 (s, 3H), 2.26 (s, 3H), 1.05-0.91 (m, 4H); ¹³CNMR (100 MHz, CDCl₃) δ 175.92, 171.51, 168.61, 156.24, 141.86, 131.02,130.19, 129.75, 127.65, 123.91, 114.81, 77.58, 77.26, 76.94, 67.14,43.44, 29.96, 21.82, 20.72, 9.29.

LC-MS (ESI+) m/z 378.18 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₄N₄O₃(M+H)⁺378.1812. found 378.1796.

SO2-145 (16a)

2-(4-Ethylphenoxy)-N-isopropyl-N-((3-pyridin-3-yl)1,2,4-oxadiazol-5-yl)methylacetamide(SO2-145) (16a): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(p-tolyloxy)propanoyl chloride (15a)(34 mg, 0.17 mmol) and ofN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (31mg, 0.14 mmol) and triethyl amine (28 mg, 0.28 mmol). The compound 16a(SO2-145) was isolated as a yellow solid. (40 mg, 75%). M.p. 87.9-89.4°C.

Chiral HPLC 47.44% (S isomer) 49.08% (R isomer) [R_(t)=63.27 min (Sisomer) R_(t)=65.88 min, 0.5% isopropanol in hexane 120 min)]; HPLC96.31% (R_(t)=14.9 min, 35% CH₃CN in 0.1% TFA water 30 min); The ¹H NMRshowed 7:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1H[δ 9.32 minor isomer shown], [δ 9.18 minor isomer shown]), 8.73 (dd,J=4.8, 1.4 Hz, 1H), 8.29 (dt, J=7.9, 2.1 Hz, 1H [δ 8.36 minor isomershown] [δ 8.20 minor isomer shown]), 7.57 (ddd, J=7.8, 4.8, 0.6 Hz, 1H),6.83 (d, J=8.5 Hz, 2H [δ 6.70 minor isomer shown]), 5.00 (q, J=6.8 Hz,1H), 4.81-4.72 (m, 1H), 4.67 (d, J_(BA)=16.76 Hz, 1H [δ 4.97 minorisomer shown]), 4.61 (d, J_(AB)=16.68 Hz, 1H [δ 4.83 minor isomershown]), 2.28 (s, 3H [δ 2.15 minor isomer shown]), 1.67 (s, 3H [δ 1.62minor isomer shown]), 1.31 (s, 3H [δ 1.19 minor isomer shown]), 1.12 (s,3H [δ 1.15 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 177.41,171.86 [δ 171.53 minor isomer shown], 166.58 [δ 166.65 minor isomershown], 155.37, 152.19 [δ 152.38 minor isomer shown], 148.92, 134.94 [δ134.88 minor isomer shown], 131.13 [δ 131.39 minor isomer shown], 130.33[δ 130.20 minor isomer shown], 123.78 [δ 123.30 minor isomer shown],115.30, 114.98 [δ 115.30 minor isomer shown], 74.69 [δ 75.11 minorisomer shown], 48.19 [δ 47.92 minor isomer shown], 37.64 [δ 39.03 minorisomer shown], 29.93 [δ 29.59 minor isomer shown], 29.59, 21.44 [δ 19.93minor isomer shown], 21.35 [δ 19.86 minor isomer shown], 20.73 [δ 20.58minor isomer shown], 18.19 [δ 18.00 minor isomer shown].

LC-MS (ESI+) m/z 381.19 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₅N₄O₃(M+H)⁺381.1921. found 381.1924.

SO3-019 (16b)

(S)—N-Isopropyl-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)propanamide(SO3-019) (16b): This compound was synthesized using the same protocolfor 11x (SO2-076) except using (S)-2-(p-tolyloxy)propanoyl chloride(15b) (34 mg, 0.17 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (31mg, 0.14 mmol) and triethyl amine (29 mg, 0.28 mmol). The compound 16b(SO3-019) was obtained as a sticky compound (41 mg, 77%).

Chiral HPLC 91.18% (R_(t)=61.67 min, 0.5% isopropanol in hexane 120min); HPLC 94.66% (R_(t)=14.3 min, 35% CH₃CN in 0.1% TFA water 20 min);The ¹H NMR showed 7:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ9.19 (s, 1H [δ 9.25 minor isomer shown], [δ 9.12 minor isomer shown]),8.67 (brs, 1H), 8.22 (dt, J=7.8 Hz, 1.8 Hz, 1H [δ 8.29 minor isomershown], [δ 8.14 minor isomer shown]), 7.34 (dd, J=7.9, 4.9 Hz, 1H), 7.00(d, J=8.5 Hz, 2H [δ 6.88 minor isomer shown]), 6.76 (d, J=8.6 Hz, 2H [δ6.63 minor isomer shown]), 4.93 (q, J=6.8 Hz, 1H), 4.74-4.65 (m, 1H),4.60 (d, J_(AB)=16.72 Hz, 1H [δ 4.89 minor isomer shown]), 4.54 (d,J_(BA)=16.72 Hz, 1H [δ 4.76 minor isomer shown]), 2.21 (s, 3H [δ 2.20minor isomer shown] [δ 2.07 minor isomer shown]), 1.60 (d, J=6.8 Hz, 3H[δ 1.66 minor isomer shown], [δ 1.55 minor isomer shown]), 1.24 (d,J=6.7 Hz, 3H [δ 1.13 minor isomer shown]), 1.12-1.07 (m, 1H), 1.05 (d,J=6.6 Hz, 3H [δ 1.09 minor isomer shown]); ¹³C NMR (101 MHz, CDCl₃) δ177.47, 171.91, 166.46, 155.35 [δ 155.67 minor isomer shown], 151.75,148.49, 135.29, 131.13 [δ 131.38 minor isomer shown], [δ 130.94 minorisomer shown], 130.33 [δ 130.22 minor isomer shown], 114.96 [δ 115.19minor isomer shown], [δ 115.27 minor isomer shown], 74.66 [δ 74.58 minorisomer shown], 48.26 [δ 48.18 minor isomer shown], 37.64 [δ 37.71 minorisomer shown] [δ 37.58 minor isomer shown] 29.93, 21.43 [δ 20.75 minorisomer shown], 21.34 [δ 20.71 minor isomer shown], 18.18 [δ 18.87 minorisomer shown] [δ 18.02 minor isomer shown].

LC-MS (ESI+) m/z 381.20 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₅N₄O₃ (M+H)⁺381.1921. found 381.1921.

SO3-065 (16c)

(R)—N-Isopropyl-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyloxy)propanamide(SO3-065): This compound was synthesized using the same protocol for 11x(SO2-076) except using (R)-2-(p-tolyloxy)propanoyl chloride (15c) (68mg, 0.34 mmol) andN-((3-pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f) (62mg, 0.28 mmol) and triethyl amine (57 mg, 0.56 mmol). The compound 16c(SO3-065) was obtained as a sticky compound (91 mg, 85%).

Chiral HPLC 97.85% (R_(t)=67.90 min, 0.5% isopropanol in hexane 120min); HPLC 97.58% (R_(t)=9.7 min, 35% CH₃CN in 0.1% TFA water 30 min);The ¹H NMR showed 7:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ9.27 (s, 1H), 8.75 (brs, 1H), 8.29 (d, J=7.9 Hz, 1H [δ 8.20 minor isomershown]), 7.46-7.39 (m, 1H), 7.06 (d, J=8.3 Hz, 1H [δ 6.94 minor isomershown]), 6.82 (d, J=8.6 Hz, 1H [δ 6.69 minor isomer shown]), 5.00 (q,J=6.8 Hz, 1H), 4.81-4.71 (m, 1H), 4.66 (d, J_(AB)=16.76 Hz, 1H [δ 4.96minor isomer shown]), 4.60 (d, J_(BA)=16.72 Hz, 1H [δ 4.82 minor isomershown]), 2.27 (s, 3H [δ 2.14 minor isomer shown]), 1.66 (d, J=6.8 Hz, 2H[δ 1.61 minor isomer shown]), 1.30 (d, J=6.7 Hz, 3H [δ 1.18 minor isomershown]), 1.12 (d, J=6.9 Hz, 1H [δ 1.15 minor isomer shown]); ¹³C NMR(101 MHz, CDCl₃) δ 177.42, 171.86 [δ 171.54 minor isomer shown], 166.56[δ 166.53 minor isomer shown], 155.36 [δ 154.88 minor isomer shown],152.16 [δ 152.35 minor isomer shown], 148.88 [δ 148.80 minor isomershown], 134.96 [δ 134.91 minor isomer shown], 131.12 [δ 131.37 minorisomer shown], 130.32 [δ 130.19 minor isomer shown], 123.81 [δ 123.29minor isomer shown], 114.96 [δ 115.28 minor isomer shown], 74.66 [δ74.60 minor isomer shown], 48.23 [δ 48.17 minor isomer shown], 37.63 [δ39.03 minor isomer shown], 29.93, 21.44 [δ 20.74 minor isomer shown], [δ19.93 minor isomer shown] 21.34 [δ 20.72 minor isomer shown] [δ 19.85minor isomer shown], 18.19 [δ 18.01 minor isomer shown].

LC-MS (ESI+) m/z 381.20 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₅N₄O₃(M+H)⁺381.1921. found 381.1922.

SO3-106 (16d)

N-Isopropyl-2-(4-propylphenoxy)-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propanamide(SO3-106) (16d): This compound was synthesized using the same protocolfor 11x (SO2-076) except using 2-(4-propylphenoxy)propanoyl chloride(15d) (71 mg, 0.31 mmol) andN-((3-pyrimidin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f)(62 mg, 0.28 mmol) and triethyl amine (57 mg, 0.56 mmol). The compound16d (SO3-106) was obtained as a pale yellow solid (92 mg, 80%). M.p.93.9-96.0. ° C.

Chiral HPLC 50.07% (S isomer) 49.94% (R isomer) [R_(t)=58.38 min (Sisomer) R_(t)=70.87 min, 0.5% isopropanol in hexane 120 min)]; HPLC97.29% (R_(t)=9.2 min, 50% CH₃CN in 0.1% TFA water 30 min); The ¹H NMRshowed 7:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.27 (s,1H), 8.74 (brs, 1H), 8.29 (dt, J=8.0 Hz, 1.8 Hz, 1H [δ 8.21 minor isomershown]), 7.41 (dd, J=7.8 Hz, 4.9 Hz, 1H), 7.07 (d, J=8.6 Hz, 2H [δ 6.96minor isomer shown]), 6.84 (d, J=8.7 Hz, 2H [δ 6.72 minor isomershown]), 5.01 (q, J=6.8 Hz, 1H), 4.80-4.70 (m, 1H), 4.66 (d,J_(AB)=16.84 Hz, 1H, [δ 4.96 minor isomer shown]), 4.62 (d, J_(BA)=16.80Hz, 1H [δ 4.84 minor isomer shown]), 2.51 (t, J=7.6 Hz, 2H [δ 2.38 minorisomer shown]), 1.66 (d, J=6.8 Hz, 3H), 1.64-1.51 (m, 2H [δ 1.53-1.44minor isomer shown]), 1.31 (d, J=6.7 Hz, 3H [δ 1.18 minor isomershown]), 1.12 (d, J=6.9 Hz, 3H [δ 1.15 minor isomer shown]), 1.12 (d,J=6.6 Hz, 2H), 0.90 (t, J=7.3 Hz, 3H, 4.64 (s, 1H [δ 0.95 minor isomershown], [δ 0.86 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 177.43,171.84 [δ 171.51 minor isomer shown], 166.56, 155.52 [δ 155.01 minorisomer shown], 152.10 [δ 152.35 minor isomer shown], 148.83, 136.04 [δ136.31 minor isomer shown], 134.94, 129.72 [δ 129.92 minor isomershown], [δ 129.59 minor isomer shown], 123.85, 114.92 [δ 115.24 minorisomer shown], [δ 114.62 minor isomer shown], 74.55 [δ 75.03 minorisomer shown], 48.20 [δ 47.87 minor isomer shown], 47.87, 37.64 [δ 39.02minor isomer shown], 37.33 [δ 37.21 minor isomer shown], 24.88 [δ 24.78minor isomer shown], 21.44 [δ 21.17 minor isomer shown], [δ 19.92 minorisomer shown], 21.33 [δ 21.02 minor isomer shown], [δ 19.84 minor isomershown], 18.21 [δ 18.00 minor isomer shown], 13.99.

LC-MS (ESI+) m/z 409.23 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₃H₂₉N₄O₃(M+H)⁺409.2234. found 409.2238.

SO3-110 (16e)

(S)—N-Isopropyl-2-(4-propylphenoxy)-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propanamide(SO3-110) (16e): This compound was synthesized using the same protocolfor 11x (SO2-076) except using (S)-2-(4-propylphenoxy)acetyl chloride(15e) (62 mg, 0.23 mmol) andN-((3-pyrimidin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f)(50 mg, 0.23 mmol) and triethyl amine (47 mg, 0.46 mmol). The compound16e (SO3-110) was obtained as a pale yellow solid (79 mg, 84%). M.p.76.7-78.8° C.

Chiral HPLC 90.58% (R_(t)=56.67 min, 0.5% isopropanol in hexane 120min); HPLC 96.01% (R_(t)=18.7 min, 45% MeOH in 0.1% TFA water 30 min);The ¹H NMR showed 7:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ9.25 (s, 1H [δ 9.30 minor isomer shown]), [δ 9.21 minor isomer shown]),8.72 (dd, J=4.9, 1.7 Hz, 1H), 8.28 (dt, J=8.0 Hz, J=2.0 Hz, [δ 8.34minor isomer shown]), [δ 8.21 minor isomer shown]), 7.40 (ddd, J=8.0,4.9, 0.8 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H [δ 6.95 minor isomer shown]),6.83 (d, J=8.7 Hz, 2H [δ 6.71 minor isomer shown]), 5.00 (q, J=6.7 Hz,2H), 4.79-4.67 (m, 1H), 4.66 (d, J_(AB)=16.84 Hz, 1H [δ 4.96 minorisomer shown]), 4.61 (d, J_(BA)=16.68 Hz, 1H [δ 4.83 minor isomershown]), 2.50 (t, J=7.6 Hz, 2H [δ 2.38 minor isomer shown]), 1.65 (d,J=6.8 Hz, 3H), 1.63-1.52 (m, 2H [δ 1.52-1.43 minor isomer shown]), 1.30(d, J=6.7 Hz, 3H [δ 1.36 minor isomer shown], [δ 1.25 minor isomershown]), 1.11 (d, J=6.6 Hz, 3H [δ 1.08 minor isomer shown], [δ 1.04minor isomer shown]), 0.90 (t, J=7.3 Hz, 3H [δ 0.95 minor isomer shown],[δ 0.85 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 177.44, 171.82[δ 171.51 minor isomer shown], [δ 172.48 minor isomer shown], 166.54 [δ166.63 minor isomer shown], 155.52 [δ 155.02 minor isomer shown], 152.15[δ 152.36 minor isomer shown], 148.85 [δ 148.78 minor isomer shown],136.00 [δ 136.26 minor isomer shown] [δ 136.08 minor isomer shown],134.89 [δ 134.96 minor isomer shown] [δ 134.86 minor isomer shown],129.70, [δ 129.90 minor isomer shown], [δ 129.56 minor isomer shown],123.78 [δ 123.89 minor isomer shown], [δ 123.82 minor isomer shown],123.28, 114.92 [δ 114.63 minor isomer shown], [δ 115.24 minor isomershown], 74.47 [δ 74.95 minor isomer shown], [δ 73.99 minor isomershown], 48.20 [δ 48.58 minor isomer shown], [δ 47.88 minor isomershown], 37.62 [δ 39.04 minor isomer shown], 37.31 [δ 37.19 minor isomershown], 24.86 [δ 24.76 minor isomer shown], 21.42 [δ 21.16 minor isomershown]), [δ 19.90 minor isomer shown]), 21.30 [δ 21.00 minor isomershown]), [δ 19.82 minor isomer shown], 18.20 [δ 18.32 minor isomershown]), [δ 17.99 minor isomer shown], 13.97 [δ 13.94 minor isomershown];

LC-MS (ESI+) m/z 409.23 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₃H₂₉N₄O₃(M+H)⁺409.2234. found 409.2250.

SO3-109 (16f)

(R)—N-Isopropyl-2-(4-propylphenoxy)-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propanamide(SO3-109) (16f): This compound was synthesized using the same protocolfor 11x (SO2-076) except using (S)-2-(4-propylphenoxy)acetyl chloride(15f) (62 mg, 0.23 mmol) andN-((3-pyrimidin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (10f)(50 mg, 0.23 mmol) and triethyl amine (47 mg, 0.46 mmol). The compound16f (SO3-109) was obtained as a pale yellow solid (77 mg, 82%). M.p.75.5-76.8° C.

Chiral HPLC 98.02% (R_(t)=81.55 min, 0.5% isopropanol in hexane 120min); HPLC 96.38% (R_(t)=18.5 min, 45% MeOH in 0.1% TFA water 30 min);The ¹H NMR showed 7:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ9.26 (s, 1H [δ 9.31 minor isomer shown]), [δ 9.19 minor isomer shown]),8.73 (dd, J=4.9, 1.6 Hz, 1H), 8.29 (dt, J=8.1 Hz, J=1.9 Hz, [δ 8.35minor isomer shown]), [δ 8.21 minor isomer shown]), 7.40 (ddd, J=8.0,4.9, 0.8 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H [δ 6.95 minor isomer shown]),6.84 (d, J=8.7 Hz, 2H [δ 6.72 minor isomer shown]), 5.01 (q, J=6.7 Hz,1H), 4.79-4.71 (m, 1H), 4.66 (d, J_(AB)=16.80 Hz, 1H [δ 4.96 minorisomer shown]), 4.62 (d, J_(BA)=16.80 Hz, 1H [δ 4.84 minor isomershown]), 2.51 (t, J=7.6 Hz, 2H [δ 2.39 minor isomer shown]), 1.66 (d,J=6.8 Hz, 3H), 1.64-1.53 (m, 2H), 1.31 (d, J=6.7 Hz, 3H [δ 1.25 minorisomer shown]), 1.12 (d, J=6.6 Hz, 3H [δ 1.08 minor isomer shown]), [δ1.04 minor isomer shown]), 0.90 (t, J=7.3 Hz, 3H); [δ 0.95 minor isomershown]), [δ 0.86 minor isomer shown]), ¹³C NMR (100 MHz, CDCl₃) δ177.42, 171.86 57 [δ 171.50 minor isomer shown]), 166.57, 155.52 [δ155.01 minor isomer shown], 152.37, 152.16 [δ 152.37 minor isomershown], 148.89 [δ 148.81 minor isomer shown], 136.05 [δ 136.32 minorisomer shown], 134.92 [δ 134.88 minor isomer shown], 129.72, [δ 129.59minor isomer shown], [δ 129.92 minor isomer shown], 123.79 [δ 123.33minor isomer shown]), 114.93 [δ 115.25 minor isomer shown] [δ 114.63minor isomer shown], 74.57 [δ 75.05 minor isomer shown], 48.20 [δ 47.88minor isomer shown]), 37.64, 37.33 [δ 37.21 minor isomer shown], 24.88[δ 24.78 minor isomer shown]), 21.44 [δ 21.17 minor isomer shown], [δ19.92 minor isomer shown], 21.33 [δ 21.02 minor isomer shown], [δ 19.84minor isomer shown], 18.21 [δ 18.00 minor isomer shown], 13.98.

LC-MS (ESI+) m/z 409.23 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₃H₂₉N₄O₃(M+H)⁺409.2234. found 409.2242.

SO2-024 (18)

1-Isopropyl-3-(4-methylbenzyl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)urea(SO2-024) (18): A solution ofisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (70 mg,0.32 mmol), 1-isocyanatomethyl-4-methyl-benzene (47 mg, 0.32 mmol) andtriethyl amine (39 mg, 0.39 mmol) were refluxed in benzene overnight.Benzene was evaporated and the residue was dissolved in ethyl acetate(20 ml) and washed with 4M HCl (3×10 ml) and water (2×20 ml). Organicsolvent was dried (MgSO₄) and evaporated, the compound 18 was purifiedby column chromatography (EtOAc:hexane gradient elution) to obtain 18(SO2-024) as a white solid (90 mg, 78%). M.p. 87.6-89.1. ° C.

HPLC 96.26% (R_(t)=14.98 min, 50% CH₃CN in 0.1% TFA water 30 min); ¹HNMR (400 MHz, CDCl₃) δ 7.96 (dd, J=8.3, 1.4 Hz, 2H), 7.56-7.49 (m, 1H),7.49-7.39 (m, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 5.52(apparent t, 1H), 4.63 (s, 2H), 4.43 (d, J=4.7 Hz, 2H), 4.40-4.34 (m,1H), 2.33 (s, 3H), 1.22 (d, J=6.8 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ177.63, 168.47, 158.01, 137.13, 136.32, 131.58, 129.52, 129.03, 128.03,127.71, 126.53, 77.62, 77.31, 76.99, 47.12, 45.27, 37.62, 21.36, 20.96.

LC-MS (ESI+) m/z 365.20 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₅N₄O₂ (M+H)⁺365.1972. found 365.1988.

SO2-090 (20)

N-Isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolylamino)acetamide(SO2-090) (20): A solution of p-toluidine (19 mg, 0.18 mmol),N-isopropyl-2-chloro-N-((3-phenyl-1,2,4-oxodiazol-5-yl)methyl)acetamide(19) (66 mg, 0.2 mmol) and sodium acetate (18 mg, 0.22 mmol) in ethanol(20 ml) were refluxed for 15 h. Ethanol was evaporated and the productwas purified by column chromatography (EtOAc:hexane gradient elution) toobtain 20 (SO2-090) as a yellow-brown sticky solid (51 mg, 78%).

HPLC 96.59% (R_(t)=12.2 min, 45% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.06(dd, J=8.0, 1.7 Hz, 2H), 7.54-7.41 (m, 3H), 7.01 (d, J=8.1 Hz, 2H), 6.59(d, J=8.3 Hz, 2H), 4.76 (s, 2H [δ 4.71 minor isomer shown]), 4.29-4.16(m, 1H [δ 4.98-4.90 minor isomer shown]), 4.05 (s, 2H), 2.25 (s, 3H [δ2.23 minor isomer shown]), 1.34 (d, J=6.6 Hz, 6H [δ 1.18 minor isomershown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.66 [δ 176.22 minor isomershown], 169.91 [δ 169.69 minor isomer shown], 168.65 [δ 168.92 minorisomer shown], 145.14, 131.43 [δ 131.83 minor isomer shown], 130.01 [δ130.14 minor isomer shown], 129.00 [δ 129.18 minor isomer shown], 127.74[δ 127.33 minor isomer shown], 126.82, 113.51 [δ 113.65 minor isomershown], 47.98 [δ 49.59 minor isomer shown], 46.18 [δ 46.74 minor isomershown], 37.25 [δ 37.44 minor isomer shown], 21.46 [δ 20.14 minor isomershown], 20.65 [δ 19.96 minor isomer shown].

LC-MS (ESI+) m/z 365.19 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₁H₂₅N₄O₂(M+H)⁺365.1972. found 365.1981.

SO2-027 (23a)

N-Isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-3-(4-(trifluoromethyl)phenyl)propanamide(SO2-027) (23a): This compound was synthesized using the same protocolfor 1 (SO1-143) except using 3-(4-trifluoromethyl)phenyl)propanoylchloride (22a) (130 mg, 0.55 mmol) andisopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine (10c) (100 mg,0.46 mmol) and triethyl amine (90 mg, 0.92 mmol). The compound 23a(SO2-027) was obtained as a white solid (168 mg, 88%). mp 96.1-97.7° C.

HPLC 97.9% (R_(t)=5.27 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.06(dd, J=7.9, 1.7 Hz, 2H), 7.63-7.42 (m, 5H), 7.37 (d, J=8.1 Hz, 2H [δ7.33 minor isomer shown]), 4.61 (s, 2H [δ 4.61 minor isomer shown]),4.25-4.18 (m, 1H [δ 4.97 minor isomer shown]), 3.08 (t, J=7.6 Hz, 2H [δ3.02 minor isomer shown]), 2.79 (t, J=7.7 Hz, 2H [δ 2.71 minor isomershown]), 1.24 (d, J=6.7 Hz, 6H [δ 1.12 minor isomer shown]); ¹³C NMR(100 MHz, CDCl₃) δ 177.07 [δ 176.66 minor isomer shown], 172.02, 171.92[δ 172.02 minor isomer shown], 168.58, 145.48, 131.40 [δ 131.84 minorisomer shown], 129.19, 129.07, 129.00 [δ 128.88 minor isomer shown],127.70 [δ 127.67 minor isomer shown], 126.94, 125.64 (q, J=3.76 Hz),124.50 (q, J=271 Hz), 48.78 [δ 45.82 minor isomer shown], 37.16 [δ 38.72minor isomer shown], 34.81 [δ 35.30 minor isomer shown], 31.09 [δ 31.17minor isomer shown], 21.33 [δ 20.20 minor isomer shown]; ¹⁹F NMR (376MHz, CDCl₃) δ −62.75, [δ −62.78 minor isomer shown].

LC-MS (ESI+) m/z 418.18 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₃F₃N₃O₂ (M+H)⁺418.1737. found 418.1745.

SO3-029 (23b)

Benzofuran-2-carboxylic acidisopropyl-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)methyl)-amide (SO3-029)(23b): This compound was synthesized using the same protocol for SO2-07611x except using benzofuran-2-carbonyl chloride (22b) (64 mg, 0.35 mmol)and N-((3-pyridin-2-yl)-1,2,4-oxadizaol-5-yl)methyl)propan-2-amine (10f)(64 mg, 0.29 mmol) and triethyl amine (59 mg, 0.58 mmol). The compound23b (SO3-029) was obtained as a sticky colorless compound (103 mg, 82%).

HPLC 94.48% (R_(t)=4.1 min, 70% MeOH in 0.1% TFA water 20 min); ¹H NMR(400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.71 (d, J=4.0 Hz, 1H), 8.32 (d, J=7.9Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.46-7.32 (m, 3H [δ 7.57-7.46 minorisomer shown]), 7.31-7.25 (m, 2H), 5.03-4.93 (m, 1H), 4.89 (s, 2H), 1.37(d, J=3.1 Hz, 6H [δ 7.50 minor isomer shown]). ¹³C NMR (101 MHz, CDCl₃)δ 166.69 50 [δ 161.31 minor isomer shown], 154.93, 152.05, 148.69,135.19, 127.05 50 [δ 126.98 minor isomer shown], 123.98 [δ 123.95 minorisomer shown], 122.63 [δ 123.26 minor isomer shown] 113.13, 112.13,49.89, 41.68, 38.21, 22.78, 21.66.

LC-MS (ESI+) m/z 363.16 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₁₉N₄O₃(M+H)⁺363.1452. found 363.1455.

SO2-091 (27)

N-Isopropyl-N-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)-2-(p-tolyloxy)acetamide(SO2-091) (24): This compound was synthesized using the same protocolfor SO1-143 1 except using p-tolyloxy-acetyl chloride (5a) (56 mg, 0.30mmol) and N-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)propan-2-amine (26)(58 mg, 0.25 mmol) and triethyl amine (51 mg, 0.50 mmol). The compound24 (SO2-091) was isolated as a sticky solid (86 mg, 87%).

HPLC 97.51% (R_(t)=22.7 min, 50% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ8.07-8.02 (m, 2H), 7.52-7.40 (m, 3H), 7.09 (d, J=8.4 Hz, 2H), 6.85 (d,J=8.6 Hz, 2H), 4.69 (s, 2H), 4.31-4.18 (m, 2H [δ 4.55-4.44 minor isomershown]), 3.72 (t, J=7.4 Hz, 2H [δ 3.89 minor isomer shown]), 3.28 (t,J=7.4 Hz, 2H), 2.28 (s, 3H [δ 2.26 minor isomer shown]), 1.28 (d, J=6.7Hz, 6H [δ 1.20 minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 177.76,168.50, 168.40, 155.99, 131.37 [δ 131.18 minor isomer shown], 130.29,129.05, 127.66 [δ 126.99 minor isomer shown], 114.59 [δ 114.67 minorisomer shown], 68.31 [δ 68.99 minor isomer shown], 48.80 [δ 47.87 minorisomer shown], 38.56 [δ 41.31 minor isomer shown], 26.18 [δ 28.64 minorisomer shown], 21.36, [δ 20.45 minor isomer shown].

20.72.

LC-MS (ESI+) m/z 380.20 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₆N₃O₃(M+H)⁺380.1969. found 380.1965.

SO2-075

N-isopropyl-N-((3-pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl-2-(p-tolyloxy)acetamide(SO2-75): This compound was synthesized using the same protocol shownfor SO1-143 except using p-tolyloxy-acetyl chloride (42 mg, 0.24 mmol),N-((3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine (42 mg,0.19 mmol) and triethylamine (38 mg, 0.54 mmol). The required compoundSO2-075 (52 mg, 75%) was obtained as a white solid. HPLC 95.31%(R_(t)=9.03, 60% CH₃CN in 0.1% TFA water 30 min); The ¹H NMR showed 3:1ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 7.99 (d,J=7.8 Hz, 1H), 7.76 (td, J=7.8, 1.6 Hz, 1H), 7.39-7.31 (m, 1H), 7.03(dd, J=8.5, 3.8 Hz, 2H [δ 6.96 minor isomer shown]), 6.80 (d, J=8.6 Hz,2H [δ 6.73 minor isomer shown]), 4.72 (s, 2H [δ 4.85 minor isomershown]), 4.70 (s, 2H [δ 4.74 minor isomer shown])), 4.40-4.31 (m, 1H),2.21 (s, 3H [δ 2.17 minor isomer shown]), 1.22 (d, J=6.6 Hz, 6H [δ 1.08minor isomer shown]). LC-MS (ES+) 366 (M+H)⁺ HRMS (ESI+ve) m/zcalculated for C₂₁H₂₄N₃O₃ (M+H)⁺366.1812. found 366.1821. LC-MS (ES+)367 (M+H)⁺ HRMS (ESI+ve) m/z calculated for C₂₀H₂₃N₄O₃ (M+H)⁺367.1765.found 367.1774.

SO2-076

N-Isopropyl-N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2-(p-tolyoxy)acetamide(SO2-076): This compound was synthesized using the same protocol shownfor SO1-143 except using p-tolyloxy-acetyl chloride (42 mg, 0.24 mmol),N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-amine (42 mg, 0.19mmol) and triethylamine (38 mg, 0.54 mmol). The required compoundSO2-076 (52 mg, 75%) was obtained as a white solid.

HPLC 99.43% (R_(t)=9.03, 60% CH₃CN in 0.1% TFA water 30 min); The ¹H NMRshowed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s,1H), 8.73 (brs, 1H), 8.28 (d, J=7.7 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H),7.08 (d, J=7.7 Hz, 2H [δ 7.02 minor isomer shown]), 6.87 (d, J=7.5 Hz,2H [δ 6.78 minor isomer shown]), 4.79 (s, 2H[δ 4.89 minor isomershown]), 4.71 (s, 2H[δ 4.80 minor isomer shown]), 2.28 (s, 3H[δ 2.23minor isomer shown]), 1.32 (d, J=6.6 Hz, 6H[δ 1.17 minor isomer shown]).

LC-MS (ES+) 366 (M+H)⁺ HRMS (ESI+ve) m/z calculated for C₂₁H₂₄N₃O₃(M+H)⁺366.1812. found 366.1821. LC-MS (ES+) 367 (M+H)⁺ HRMS (ESI+ve) m/zcalculated for C₂₀H₂₃N₄O₃ (M+H)⁺367.1765. found 367.1774.

SO2-065

5-(Chloromethyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole (SO2-065): To asolution of N-hydroxypicolinimidamide (0.2 g, 1.5 mmol) in DCM (20 ml)and chloroacetyl chloride (0.2 g, 1.8 mmol) at 0° C.,diisopropylethylamine (0.23 g, 1.8 mmol) was added (dropwise). Themixture was warmed up to r.t. and stirred for 24 h. and organic solventwas evaporated and the residue was refluxed overnight in toluene (20 mL)to complete the cyclization. The product obtained was purified usingSiO₂ chromatography (EtOAc:hexane gradient elution). The requiredcompound SO2-065 (0.24 g, 81%) was obtained as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.81 (ddd, J=4.8, 1.6, 1.0 Hz, 1H), 8.14 (d,J=7.9 Hz, 1H), 7.87 (ddd, J=7.9 Hz, 4.8, 1.8 Hz, 1H), 7.46 (ddd, J=7.7,4.8, 1.2 Hz, 1H), 4.79 (s, 2H).

SO2-055

5-(Chloromethyl)-3-(pyridine-3-yl)-1,2,4-oxadiazole (SO2-055): Thiscompound was synthesized using the same protocol shown for SO2-065except using N-hydroxynicotinimidamide (0.3 g, 2 mmol), chloroacetylchloride (0.29 g, 2.6 mmol) at 0° C., diisopropylethylamine (0.34 g, 2.6mmol) The compound SO2-055 (0.29 g, 73%) was obtained as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 9.25 (dd, J=2.2, 0.9 Hz, 1H), 8.70 (dd, J=4.9,1.7 Hz, 1H), 8.34-8.24 (m, 1H), 7.38 (ddd, J=8.0, 4.9, 0.9 Hz, 1H), 4.71(s, 2H).

SO2-071

N-((3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine(SO2-071): This compound was synthesized using the same protocol shownfor SO1-142 except using5-(Chloromethyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole (75 mg, 0.38 mmol),isopropylamine (34 mg, 0.58 mmol) and potassium carbonate (109 g, 1.9mmol). The compound SO2-071 (75 mg, 89%) was obtained as a viscousliquid.

¹H NMR (400 MHz, CDCl₃) δ 8.80 (ddd, J=4.8, 1.7, 0.9 Hz, 1H), 8.13 (dt,J=7.9, 1.0 Hz, 1H), 7.85 (td, J=7.8, 1.8 Hz, 1H), 7.43 (ddd, J=7.6, 4.8,1.2 Hz, 1H), 4.15 (s, 2H), 3.00-2.83 (m, 1H), 1.11 (d, J=6.2 Hz, 6H).

SO2-060

N-((3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)propan-2-amine (SO2-060):This compound was synthesized using the same protocol shown for SO1-142except using 5-(Chloromethyl)-3-(pyridine-3-yl)-1,2,4-oxadiazole (80 mg,0.41 mmol), isopropylamine (48 mg, 8.18 mmol) and potassium carbonate(2.8 g, 2 mmol). The compound SO2-060 (75 mg, 84%) was obtained as ayellowish solid.

¹H NMR (400 MHz, CDCl₃)) δ 9.25 (d, J=1.4 Hz, 1H), 8.68 (dd, J=4.8, 1.6Hz, 1H), 8.32-8.25 (m, 1H), 7.36 (ddd, J=7.9, 4.9, 0.8 Hz, 1H), 4.08 (s,2H), 2.98-2.75 (m, 1H), 1.07 (d, J=6.2 Hz, 6H).

SO2-051 (10q)

N-((3-phenyl-1,2,4-oxadiazol-5yl)methycyclopropanamine (SO2-051) (10q):This compound was synthesized using the same protocol for 10a (SO1-142)except using 5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole (9c) (80 mg, 0.41mmol) and cyclopropyl amine (50 mg, 0.82 mmol) and potassium carbonate(0.28 g, 2.1 mmol). The compound SO2-051 10q was obtained as a whitesolid (75 mg, 85%). ¹H NMR (400 MHz, CDCl₃) δ 8.13-7.96 (m, 2H),7.53-7.34 (m, 3H), 4.09 (d, J=2.6 Hz, 2H), 2.32-2.14 (m, 1H), 0.57-0.29(m, 4H).

SO2-054 (32)

N-cyclopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-2-(4-(trifluoromethyl)phenoxy)acetamide(SO2-054) (32): This compound was synthesized using the same protocolfor 1 (SO1-143) except using (4-trifluoromethyl-phenoxy)-acetyl chloride(5b) (140 mg, 0.52 mmol) andN-((3-phenyl-1,2,4-oxadiazol-5yl)methycyclopropanamine (10q) (75 mg,0.35 mmol) and triethyl amine (71 mg, 0.70 mmol). The compound SO2-05432 was obtained as a white solid (106 mg, 73%).

HPLC 97.4% (R_(t)=10.1 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 4:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.04(dd, J=8.1, 1.6 Hz, 2H), 7.62-7.39 (m, 5H), 7.02 (d, J=8.5 Hz, 2H), 5.07(s, 2H [δ 4.73 minor isomer shown]), 4.89 (s, 2H [δ 4.71 minor isomershown]), 3.11-3.06 (m, 1H [δ 3.42-3.37 minor isomer shown]), 1.08-0.94(m, 4H [δ 1.22, 1.14 minor isomer shown]); HRMS (ESI+ve) m/z calculatedfor C₂₁H₁₉F₃N₃O₃ (M+H)⁺418.1373. found 418.1378.

SO3-010 (33)

4-(Chloromethyl)-2-phenyloxazole (SO3-010) (33): To a solution ofdichloroacetone (250 mg, 1.97 mmol) in toluene (5 ml) was addedbenzamide (120 mg, 0.99 mmol) and heated at 120° C. for 14 h. Toluenewas evaporated and the compound was purified by column chromatography(gradient elution with EtOAc:Hexane). Compound 33 (SO3 010) was obtainedas a viscous liquid. (141 mg, 74%). ¹H NMR (400 MHz, CDCl₃) δ 8.11-7.92(m, 2H), 7.69 (s, 1H), 7.45 (d, J=2.6 Hz, 3H), 4.57 (s, 2H).

SO3-022 (34)

N-((2-phenyloxazol-4-yl)methyl)propan-2-amine (SO3-022) (34): A solutionof 4-(chloromethyl)-2-phenyloxazole (33) (SO3-010) (120 mg, 0.62 mmol),isopropyl amine (73 mg, 12.40 mmol) and potassium carbonate (428 mg,31.00 mmol) in acetonitrile (20 ml) were refluxed for 4 h. Acetonitrilewas evaporated and the residue was dissolved in ethyl acetate (20 ml)and washed with water (3×20 ml). Organic solvent was dried (MgSO₄) andevaporated to obtain SO3-022 34 as a brown viscous liquid. (121 mg,90%). ¹H NMR (400 MHz, CDCl₃) δ 8.06-7.86 (m, 2H), 7.54 (s, 1H), 7.37(d, J=2.3 Hz, 3H), 3.72 (s, 2H), 2.91-2.82 (m, 1H), 1.07 (d, J=6.3 Hz,6H).

SO3-023 (35)

N-Isopropyl-N-((2-phenyloxazol-4-yl)methyl)-2-(p-tolyloxy)acetamide(SO3-023) (35): This compound was synthesized using the same protocolfor 1 (SO1-143) except using p-tolyloxy-acetyl chloride (61 mg, 0.33mmol) and N-((2-phenyloxazol-4-yl)methyl)propan-2-amine (SO3-022) (34)(60 mg, 0.28 mmol) and triethyl amine (57 mg, 0.56 mmol). The compoundSO3-023 35 was isolated as a white solid (84 mg, 86%). mp 126.7-127.6°C.

HPLC 100% (R_(t)=8.4 min, 60% CH₃CN in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 8.08-7.95 (m, 2H), 7.49 (s, 1H [δ 7.53 minor isomershown]), 7.48-7.40 (m, 3H), 7.08 (d, J=8.2 Hz, 2H [δ 7.05 minor isomershown]), 6.86 (d, J=8.6 Hz, 2H [δ 6.89 minor isomer shown]), 4.89 (s, 2H[δ 4.72 minor isomer shown]), 4.46 (s, 2H [δ 4.43 minor isomer shown]),4.32-4.24 (m, 1H), 2.27 (s, 3H [δ 2.23 minor isomer shown]), 1.28 (d,J=6.6 Hz, 6H [δ 1.17 minor isomer shown]). ¹³C NMR (101 MHz, CDCl₃) δ168.08 [δ 168.59 minor isomer shown], 160.80 [δ 162.37 minor isomershown], 156.01 [δ 156.35 minor isomer shown], 140.29 [δ 137.54 minorisomer shown], 139.28 [δ 135.32 minor isomer shown], 131.18, 130.93,130.65 [δ 130.82 minor isomer shown], 130.25 [δ 130.14 minor isomershown], 128.99 [δ 129.06 minor isomer shown], 126.59 [δ 126.66 minorisomer shown], 114.69 [δ 114.86 minor isomer shown], 68.14 [δ 67.98minor isomer shown], 48.94 [δ 47.07 minor isomer shown], 37.24 [δ 39.04minor isomer shown], 21.71 [δ 20.43 minor isomer shown], 20.71.

LC-MS (ESI+) m/z 365.19 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₅N₂O₃ (M+H)⁺365.1860. found 365.1872.

SO2-083 (36)

2-(4-(1H-benzo[d][1,2,3]triazole-1-carbonyl)phenoxy)-N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamideSO2-083 (36): To a solution of benzotriazole (130 mg, 1.09 mmol) in THF(10 ml) was added thionyl chloride (35 mg, 0.30 mmol) and the mixturewas stirred at rt for 30 min.4-(2-(Isopropyl((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethoxy)benzoicacid (SO2-089) (11t) (108 mg, 0.27 mmol) in THF (3 ml) was added slowlyand the mixture was stirred at rt for 5 h. THF was evaporated and theresidue was dissolved in ethyl acetate (10 ml) and washed with 4M HCl(4×10 ml) and water (2×10 ml). Organic solvent was dried (MgSO₄) andevaporated to obtain the compound SO2-083 36 as a white solid (102 mg,70%).

¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=8.3 Hz, 1H), 8.28 (d, J=8.8 Hz,2H), 8.17 (d, J=8.3 Hz, 1H), 8.09 (dd, J=7.8, 1.4 Hz, 1H), 8.00 (dd,J=6.5, 2.9 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.57-7.48 (m, 2H), 7.44-7.39(m, 2H), 7.14 (d, J=8.8 Hz, 2H), 4.96 (s, 2H [δ 5.03 minor isomershown]), 4.74 (s, 2H [δ 4.82 minor isomer shown]), 4.44-4.33 (m, 1H),1.35 (d, J=6.6 Hz, 6H [δ 1.18 minor isomer shown]).

SO2-104 (37)

2-(4-(2-(Isopropyl((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)amino)-2-oxoethoxy)benzamido)-4-methylpentanoicacid (SO2-104) (37): To a solution of leucine (24 mg, 0.18 mmol) andtriethyl amine (18 mg, 0.18 mmol) in acetonitrile:water (5:2) at 0° C.was added2-(4-(1H-benzo[d][1,2,3]triazole-1-carbonyl)phenoxy)-N-isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)acetamide(SO2-083) (36) (60 mg, 0.12 mmol) and warmed up to rt and stirred for 1h. Acetonitrile was evaporated and the residue was dissolved in ethylacetate (15 ml) and washed with 4M HCl (3×15 ml) and water (2×15 ml).Organic solvent was dried (MgSO₄) and evaporated to give SO2-104 37 as asticky solid. (44 mg, 72%).

HPLC 94.78% (R_(t)=7.5 min, 50% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d,J=7.4 Hz, 2H [δ 8.02 minor isomer shown]), 7.74 (d, J=8.8 Hz, 2H [δ 7.70minor isomer shown]), 7.52-7.41 (m, 3H), 6.98 (d, J=8.8 Hz, 2H [δ 6.93minor isomer shown]), 4.88 (s, 2H [δ 4.93 minor isomer shown]),4.77-4.72 (m, 1H), 4.71 (s, 2H [δ 4.80 minor isomer shown]), 4.41-4.36(m, 1H), 1.83-1.64 (m, 3H), 1.31 (d, J=6.6 Hz, 6H [δ 1.15 minor isomershown]), 0.96 (d, J=5.9 Hz, 6H [δ 0.89 minor isomer shown]); ¹³C NMR(100 MHz, CDCl₃) δ 176.37, 176.30, 168.55, 167.96, 167.56, 160.95 [δ160.90 minor isomer shown], 131.91, 131.51, 129.40 [δ 129.33 minorisomer shown], 129.03 [δ 129.22 minor isomer shown], 127.68, 127.06 [δ127.01 minor isomer shown], 126.71, 114.83 [δ 114.77 minor isomershown], 67.44 [δ 67.96 minor isomer shown], 51.65, 49.02 [δ 47.02 minorisomer shown], 41.27, 38.42, 37.25 [δ 38.42 minor isomer shown], 29.94,25.19, 23.11, 22.14, 21.46 [δ 19.97 minor isomer shown].

LC-MS (ESI+) m/z 509.23 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₇H₃₃N₄O₆ (M+H)⁺509.2395. found 509.2381.

SO2-121 (38)

2-((Isopropylamino)methyl)isoindoline-1,3-dione (SO2-121) (38): Thiscompound was synthesized using the same protocol for SO1-142 10a exceptusing 2-(chloromethyl)isoindoline-1,3-dione (300 mg, 1.81 mmol),isopropyl amine (160 mg, 0.272 mmol) and potassium carbonate (125 mg,9.05 mmol). The compound SO2-121 38 was isolated as a white solid (315mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.21 (m, 4H), 4.09 (s, 2H),2.90 (hept, J=6.3 Hz, 1H), 1.11 (d, J=6.3 Hz, 6H).

SO2-126 (39)

N-((1H-benzo[a′]imidazol-2-yl)methyl-N-isopropyl-2-(p-tolyloxy)acetamide(SO2-126) (38): This compound was synthesized using the same protocolfor SO1-143 except using p-tolyloxy-acetyl chloride (5a) (72 mg, 0.38mmol) and N-((1H-benzo[a′]imidazol-2-yl)methyl)propan-2-amine (38) (60mg, 0.32 mmol) and triethyl amine (65 mg, 0.64 mmol). The compoundSO2-126 39 was isolated as a white solid (95 mg, 88%). M.p. 143.0-145.2°C.

HPLC 98.95% (R_(t)=6.0 min, 50% CH₃CN in 0.1% TFA water 30 min); ¹H NMR(400 MHz, CDCl₃) δ 10.22 (s, 1H), 7.25-7.20 (m, 4H), 7.10 (d, J=8.5 Hz,2H), 6.85 (d, J=8.6 Hz, 2H), 4.78 (s, 1H), 4.72 (s, 2H), 4.34-4.04 (m,1H), 2.30 (s, 3H), 1.30 (d, J=6.6 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ170.04, 155.78, 152.04, 131.53, 130.38, 123.09, 114.59, 77.57, 77.46,77.26, 76.94, 67.47, 49.69, 39.49, 21.39, 20.73.

LC-MS (ESI+) m/z 338.19 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₀H₂₃N₃O₂(M+H)⁺338.1863. found 338.1866.

SO2-144 (40)

N-Isopropyl-N-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl-2-(p-tolyl)propanamide(SO2-144) (40): This compound was synthesized using the same protocolfor SO1-143 1 except using 2-(p-tolyloxy)propanoylchloride (5a) (19 mg,0.98 mmol) and isopropyl-(3-phenyl)-[1,2,4]oxadiazol-5-ylmethyl)-amine(10c) (177 mg, 0.82 mmol) and triethyl amine (17 mg, 1.64 mmol). Thecompound SO2-144 40 was isolated as a white solid (23 mg, 74%). mp109.0-110.0° C.

HPLC 99.77% (R_(t)=10.6 min, 60% CH₃CN in 0.1% TFA water 30 min); The ¹HNMR showed 3:1 ratio of atropisomers: ¹H NMR (400 MHz, CDCl₃) δ 8.03(dd, J=8.0, 1.6 Hz, 2H [δ 7.99 minor isomer shown]), 7.53-7.42 (m, 3H),7.07 (d, J=8.6 Hz, 2H [δ 6.98 minor isomer shown]), 6.84 (d, J=8.6 Hz,2H [δ 6.80 minor isomer shown], [δ 6.78 minor isomer shown]), 5.00 (q,J=6.8 Hz, 1H), 4.82-4.70 (m, 1H), 4.67 (d, J_(AB)=16.72 Hz, 1H [δ 4.90minor isomer shown]), 4.62 (d, J_(BA)=16.72 Hz, 1H [δ 4.83 minor isomershown]), 2.28 (s, 3H, [δ 2.18 minor isomer shown]), 1.67 (d, J=6.8 Hz,3H [δ 1.62 minor isomer shown], [δ 1.57 minor isomer shown]), 1.30 (d,J=6.7 Hz, 3H [δ 1.17 minor isomer shown]), 1.11 (d, J=6.6 Hz, 3H [δ 1.14minor isomer shown]); ¹³C NMR (100 MHz, CDCl₃) δ 176.79, 171.79 [δ171.44 minor isomer shown], 168.49, 155.44 [δ 154.92 minor isomershown], 131.33 [δ 131.63 minor isomer shown], 131.04, 130.33 [δ 130.24minor isomer shown], 128.95 [δ 129.07 minor isomer shown], 127.71 [δ127.69 minor isomer shown], 127.00, 115.02 [δ 115.45 minor isomershown], 74.80 [δ 74.66 minor isomer shown], 48.16 [δ 47.72 minor isomershown], 37.57 [δ 38.83 minor isomer shown], 21.42 [δ 19.93 minor isomershown], 21.34 [δ 19.88 minor isomer shown], 20.74 [δ 20.64 minor isomershown], 18.25 [δ 17.92 minor isomer shown].

LC-MS (ESI+) m/z 380.21 (M+H)⁺; HRMS (ESI+ve) m/z calculated forC₂₂H₂₆N₃O₃ (M+H)⁺380.1969. found 380.1975.

4.62 HPLC > 99%

>10 HPLC = 99.6%

>10 HPLC = 99.25%

0.21 0.28 0.245 ± 0.05 (n = 2) HPLC = 95.49%

6.37

>10

>10

2.66 3.63 3.145 ± 0.69 (n = 2)

0.12 0.15 0.135 ± 0.021 (n = 2)

The modifications disclosed herein indicate that the activity issensitive to changes around the amide moiety. Additionally, along withthe modifications on the rings A and B, modifications on the oxadiazolering will be used to improve the in vitro activity. The syntheticmodifications also include introduction of a chiral center around theamide moiety to further characterize this class of compounds asproteasome inhibitors.

In the preceding specification, all documents, acts, or informationdisclosed do not constitute an admission that the document, act, orinformation of any combination thereof was publicly available, known tothe public, part of the general knowledge in the art, or was known to berelevant to solve any problem at the time of priority.

The disclosures of all publications cited above are expresslyincorporated herein by reference, each in its entirety, to the sameextent as if each were incorporated by reference individually.

While there has been described and illustrated specific embodiments ofproteasome inhibitors, it will be apparent to those skilled in the artthat variations and modifications are possible without deviating fromthe broad spirit and principle of the present invention. It is also tobe understood that the following claims are intended to cover all of thegeneric and specific features of the invention herein described, and allstatements of the scope of the invention which, as a matter of language,might be said to fall therebetween.

What is claimed is:
 1. A compound of formula I:

wherein R_(A) is

Wherein R1 is H, ethyl, isopropyl, propyl, isobutyl, Br, Ph, F,ortho-CH₃, meta-CH₃, para-CH₃, CF₂H, CF₃, F, Cl, Br, NH₂, CN, OX, OH,C₆H₁₆, C₆H₁₃, C₅H₁₁, C₄H₉, C₃H₇, or NO₂; wherein R₄ is H, alkyl methyl,aryl methyl, OH, OCH₃, or NH₂; where X is an aryl or alkyl; wherein R₃is H, isopropyl, or isobutyl; wherein R_(B) is

wherein R_(C) is a heterocyclic aromatic five-member ring structure,wherein the heterocyclic aromatic five-member ring structure furthercomprises at least one heteroatom consisting of O, N, or S; WhereinR_(D) is H, alkyl, OH, or OX; where X is an aryl or alkyl; and where R₁and R₃ are not concurrently R₁=CH₃, ethyl, or CH₂(CH₃)₂, andR₃=CH₂(CH₃)₂.
 2. The compound of claim 1, wherein R_(A) is


3. The compound of claim 2, wherein R₁ is para-CH₃, CF₃, Cl, C₃H₇, C₄H₉,propyl, or isobutyl.
 4. The compound of claim 1, wherein R_(C) is


5. The compound of claim 3, further comprising: wherein R₁ is para-CH₃,CF₃, or Cl; wherein R₃ is CH₂(CH₃)₂, or CH₂CH(CH₃)₂; wherein R₄ is H;and wherein R₅ is H.
 6. The compound of claim 1, wherein the compound isan S-enantiomer.
 7. A compound; comprising formula II:

wherein R₁ is either ortho-CH₃, meta-CH₃, para-CH₃, CF₂H CF₃, F, Cl, Br,OH, NH₂, CN, NO₂, C₆H₁₀, C₆H₁₃, C₅H₁₁, C₄H₉, C₃H₇, OX, or H; wherein R₁is CH(CH₃)₂, cyclopropyl, CH₂CH(CH₃)₂, CH₂CH₃, OH, or H; wherein R_(C)is a heterocyclic ring structure; wherein R_(A) is alkyl methyl, arylmethyl, OH, OMe, or NH₂; Wherein R_(D) is H, alkyl, OH, OX, where R_(D)and R_(C) are not concurrently R_(D)=H and R_(C)=phenyl oxadiazole or asubstituted phenyl oxadiazole; where X is an alkyl or aryl; and Where R₁and R₃ are not concurrently R₁=CH₃, or CH₂(CH₃), and R₃=CH₂(CH₃).
 8. Thecompound of claim 7, wherein R_(C) is


9. The compound of claim 8, wherein R_(B) is


10. The compound of claim 8, wherein R_(C) has the structure

wherein R₆ is ortho CH₃, meta CH₃, para CH₃, CF₃, OH, NH₂, CN, NO₂, OX,Cl, or H; where X is an alkyl or arylCH₃.
 11. The compound of claim 9,wherein R₁ and R₂ are not the same group.
 12. The compound of claim 10,wherein R₁ and R₆ are not the same group.
 13. The compound of claim 7,wherein the compound is an S-enantiomer.
 14. A method of inhibiting thechymotrypsin-like activity of proteasome, comprising: administering atherapeutically effective amount of a proteasome inhibitor, Wherein theproteasome inhibitor is a compound of formula I:

wherein R_(A) is

wherein R₁ is H, ethyl, isopropyl, propyl, isobutyl, Br, Ph, F,ortho-CH₃, meta-CH₃, para-CH₃, CF₂H, CF₃, F, Cl, Br, NH₂, CN, OX, OH,C₆H₁₀, C₆H₁₃, C₅H₁₃, C₉H₉, C₃H₇, or NO₂; wherein R₄ is H, alkyl methyl,aryl methyl, OH, OCH₃, or NH₂; where X is an aryl or alkyl; wherein R₃is H, isopropyl, or isobutyl; wherein R_(B) is

wherein R_(C) is a heterocyclic aromatic five-member ring structure,where the heterocyclic aromatic five-member ring structure furthercomprises at least one heteroatom consisting of O, N, or S; WhereinR_(D) is H, alkyl, OH, or OX; where X is an aryl or alkyl; and where R₁and R₃ are not concurrently R₃=CH₃, ethyl, or CH₂(CH₃)₂, andR₃=CH₃(CH₃)₂.
 15. The proteasome inhibitor of claim 1, wherein R_(A) is


16. The proteasome inhibitor of claim 15, wherein R₁ is para-CH₃, CF₃,propyl, Cl, C₃H₇, C₄H₉, or isobutyl.
 17. The proteasome inhibitor ofclaim 16, wherein R₁ and R₃ are not the same group.
 18. The proteasomeinhibitor of claim 14, wherein R_(C) is


19. The proteasome inhibitor of claim 16, further comprising: wherein R₁is para-CH₃, CF₃, or Cl; wherein R₃ is CH₂(CH₃)₂, or CH₂CH(CH₃)₂;wherein R₄ is H; wherein R₅ is H; and wherein R₂ is H, Cl, CF₃, or CH₃.20. The method of claim 14, wherein the compound is an S-enantiomer.